Ester substituted ion channel blockers and methods for use

ABSTRACT

The invention provides compounds of Formula (I), or pharmaceutically acceptable salts thereof: 
     
       
         
         
             
             
         
       
     
     The compounds, compositions, methods and kits of the invention are useful for the treatment of pain, itch, and neurogenic inflammation.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/815,962 filed on Mar. 11, 2020, which claims the benefit of U.S.Provisional Application Ser. No. 62/816,441 filed Mar. 11, 2019, U.S.Provisional Application Ser. No. 62/931,599 filed Nov. 6, 2019, U.S.Provisional Application Ser. No. 62/816,434 filed Mar. 11, 2019 and U.S.Provisional Application Ser. No. 62/931,590 filed Nov. 6, 2019. Theentire contents of the above applications are incorporated by referenceherein.

TECHNICAL FIELD

The present invention relates generally to compounds, pharmaceuticalcompositions, and methods useful as selective inhibitors of pain, cough,and itch sensing neurons (nociceptors, cough receptors and pruriceptors)and in the treatment of neurogenic inflammation.

BACKGROUND OF THE INVENTION

The invention features compounds, compositions and methods for theselective inhibition of sensory neurons (nociceptors, cough receptorsand pruriceptors) and the treatment of neurogenic inflammation bytargeting nociceptors with a small molecule drug, while minimizingeffects on non-nociceptive neurons or other types of cells. According tothe method of the invention, small, cationic drug molecules gain accessto the intracellular compartment of sensory neurons via entry throughlarge pore receptor/ion channels that are present in pain- cough- anditch-sensing neurons but to a lesser extent or not at all in other typesof neurons or in other types of tissue.

Local anesthetics such as lidocaine and articaine act by inhibitingvoltage-dependent sodium channels in neurons. These anesthetics blocksodium channels and thereby the excitability of all neurons, not justpain-sensing neurons (nociceptors). Thus, while the goal of topical orregional anesthesia is to block transmission of signals in nociceptorsto prevent pain, administration of local anesthetics also producesunwanted or deleterious effects such as general numbness from block oflow threshold pressure and touch receptors, motor deficits and/orparalysis from block of motor axons and other complications from blockof autonomic fibers. Local anesthetics are relatively hydrophobicmolecules that gain access to their blocking site on the sodium channelby diffusing through the cell membrane. Charged derivatives of thesecompounds, which are not membrane-permeable, have no effect on neuronalsodium channels when applied to the external surface of the nervemembrane but can block sodium channels if somehow introduced inside thecell, for example, by diffusion from a micropipette used for whole-cellelectrophysiological recording from isolated neurons. Pain-, cough-, anditch-sensing neurons differ from other types of neurons in expressing(in most cases) the TRPV1 receptor/channel, which is activated bypainful heat or by capsaicin, the pungent ingredient in chili pepper.Other types of channels selectively expressed in various types ofpain-sensing, cough-sensing and itch-sensing (pruriceptor) neuronsinclude, but are not limited to, TRPV2-4, TRPA1, TRPM8, ASIC andP2X(2/3) channels. It is well established that some cationic smallmolecules such as QX-314 are able to enter a cell via passage throughactivated large pore channels such as TRPV1.

Neuropathic, inflammatory, and nociceptive pain differ in theiretiology, pathophysiology, diagnosis, and treatment. Nociceptive painoccurs in response to the activation of a specific subset of highthreshold peripheral sensory neurons, the nociceptors, by intense ornoxious stimuli. It is generally acute, self-limiting and serves aprotective biological function by acting as a warning of potential oron-going tissue damage. It is typically well-localized. Examples ofnociceptive pain include, but are not limited to, traumatic or surgicalpain, labor pain, sprains, bone fractures, burns, bumps, bruises,injections, dental procedures, skin biopsies, and obstructions.

Inflammatory pain is pain that occurs in the presence of tissue damageor inflammation including postoperative (i.e. pain associated with acuteperioperative pain resulting from inflammation caused by tissue trauma(e.g., surgical incision, dissection, burns) or direct nerve injury(e.g., nerve transection, stretching, or compression)), post-traumaticpain, arthritic pain (rheumatoid; or osteoarthritis (i.e. joint pain andstiffness due to gradual deterioration of the joint cartilage; riskfactors include aging, injury, and obesity; commonly affected joints arethe hand, wrist, neck, knee, hip, and spine)), pain and pain associatedwith damage to joints, muscle, and tendons as in axial low back pain(i.e. a prevalent, painful condition affecting the lower portion of theback; common causes include muscle strain, spine fracture, bulging orruptured disc, and arthritis), severe nociceptive pain may transition toinflammatory pain if there is associated tissue injury.

Neuropathic pain is a common type of chronic, non-malignant pain, whichis the result of an injury or malfunction in the peripheral or centralnervous system and serves no protective biological function. It isestimated to affect more than 1.6 million people in the U.S. population.Neuropathic pain has many different etiologies, and may occur, forexample, due to trauma, surgery, herniation of an intervertebral disk,spinal cord injury, diabetes, infection with herpes zoster (shingles),HIV/AIDS, late-stage cancer, amputation (including mastectomy), carpaltunnel syndrome, chronic alcohol use, exposure to radiation, and as anunintended side-effect of neurotoxic treatment agents, such as certainanti-HIV and chemotherapeutic drugs. Peripheral neuropathy is caused bydamages to the peripheral nerves from injury, trauma, prolongedpressure, or inflammation causing numbness and pain in correspondingareas of the body.

Neuropathic pain is frequently described as “burning,” “electric,”“tingling,” or “shooting” in nature. It is often characterized bychronic dynamic allodynia (defined as pain resulting from a movingstimulus that does not ordinarily elicit a painful response, such aslight touch) and hyperalgesia (defined as an increased sensitivity to anormally painful stimulus) and may persist for months or years beyondthe apparent healing of any damaged tissues.

Pain may occur in patients with cancer, which may be due to multiplecauses; inflammation, compression, invasion, metastatic spread into boneor other tissues.

There are some conditions where pain occurs in the absence of a noxiousstimulus, tissue damage or a lesion to the nervous system, calleddysfunctional pain and these include but are not limited tofibromyalgia, tension type headache, and irritable bowel disorders.

Migraine is a headache associated with the activation of sensory fibersinnervating the meninges of the brain.

Itch (pruritus) is a dermatological condition that may be localized andgeneralized and can be associated with skin lesions (rash, atopiceczema, wheals). Itch accompanies many conditions including but notlimited to stress, anxiety, UV radiation from the sun, metabolic andendocrine disorders (e.g., liver or kidney disease, hyperthyroidism),cancers (e.g., lymphoma), reactions to drugs or food, parasitic andfungal infections, allergic reactions, diseases of the blood (e.g.,polycythemia vera), and dermatological conditions. Itch is mediated by asubset of small diameter primary sensory neurons, the pruriceptor, thatshare many features of nociceptor neurons, including, but not limitedto, expression of TRPV1 channels, and other large pore channels (e.g.TRPV2-4, TRPA1, TRPM8, ASIC and P2X(2/3). Certain itch mediators, suchas eicosanoids, histamine, bradykinin, ATP, and various neurotrophinshave endovanilloid functions. Topical capsaicin suppresseshistamine-induced itch. Pruriceptors like nociceptors are therefore asuitable target for this method of delivering ion channel blockers.

Cough is a defensive reflex designed to protect the airway from foreignbodies and to aid in the clearance of luminal debris. This reflex,however, can became aberrant in a number of diseases leading to anon-productive dry cough where hyper- or allo-tussive states exist.Hyper- and allo-tussive states are often chronic in nature lastinggreater than three months and can be manifested in many airway diseasesstates including asthma, COPD, asthma-COPD overlap syndrome (ACOS),interstitial pulmonary fibrosis (IPF) and lung cancer. In addition,inappropriate cough reflexes can be manifested acutely and chronicallyfollowing viral infection. Furthermore, chronic cough can be idiopathicin nature with unknown etiology.

Neurogenic inflammation is a mode of inflammation mediated by theefferent (motor) functions of sensory neurons, in which pro-inflammatorymediator molecules released in the periphery by pain-sensing neurons(nociceptors) both activate a variety of inflammatory pathways in immunecells, and also act on the vascular system to alter blood flow andcapillary permeability.

Neurogenic inflammation contributes to the peripheral inflammationelicited by tissue injury, autoimmune disease, infection, allergy,exposure to irritants in a variety of tissues, and is thought to play animportant role in the pathogenesis of numerous disorders (e.g. migraine,arthritis, rhinitis, gastritis, colitis, cystitis, and sunburn). One wayto reduce neurogenic inflammation is to block excitability innociceptors, thereby preventing the activation of nociceptor peripheralterminals and the release of pro-inflammatory chemicals.

Despite the development of a variety of therapies for pain, itch, andneurogenic inflammation, there is a need for additional agents.

SUMMARY OF THE INVENTION

The present invention provides compounds represented by Formula (I) thatcan be used to inhibit nociceptors and/or to treat or prevent pain,itch, and neurogenic inflammation:

wherein:

Y⁻ is a pharmaceutically acceptable anion;

R^(A) is CO₂R^(T);

R^(T) is substituted or unsubstituted alkyl (preferably methyl orethyl);

R^(B) is H, D, halogen, or substituted or unsubstituted alkyl;preferably methyl or ethyl;

R^(C) is selected from as H, D, halogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, OR^(I), CN, NR^(J)R^(K),NR^(L)C(O)R^(M), S(O)R^(N), S(O)₂R^(N), SO₂R^(O)R^(P), SO₂NR^(Q)R^(R),SO₃R^(S), CO₂R^(T); C(O)R^(U), and C(O)NR^(V)R^(W), (preferably H, F,Cl, or CN and more preferably H);

each of R^(I), R^(J), R^(K), R^(L), R^(M), R^(N), R^(O), R^(P), R^(Q),R^(R), R^(S), R^(U), R^(V), and R^(W) is independently selected from H,D, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl; R^(J) and R^(K) or R^(V) and R^(W) or R^(Q) and R^(R)can also be taken together with the nitrogen to which they are attachedto form a substituted or unsubstituted 5, 6, 7, or 8 membered ring;

X¹ can be selected from —CR^(X)R^(Y)—, —NR^(Z)C(O),—NR^(Z)C(O)CR^(X)R^(Y)—, —OC(O)—, —SC(O)—, —C(O)NR^(1A)—, —C(O)O—,—C(O)—, —(O)CS—, —NR^(1A)S(O)—, —S(O)NR^(1A)—, —NR^(1A)C(O)NR^(1A)—,—S(O)— and —S(O)₂—; and each of R^(X), R^(Y), R^(Z), and R^(1A) isindependently selected from H, D, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, and substituted or unsubstitutedalkynyl. In a preferred embodiment, X¹ is —NR^(Z)C(O)—. In additionalpreferred embodiments, R^(Z) is hydrogen. In yet an additional preferredembodiment, X¹ is —NR^(Z)C(O)— and R^(Z) is hydrogen. In certainpreferred embodiments, X is —NHC(O)—;

R^(Z) is H, D, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, andsubstituted or unsubstituted heteroalkyl (preferably H);

each of R^(D) and R^(E) is independently selected from H, D, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheteroalkyl, and substituted or unsubstituted cycloalkyl;

or R^(D) and R^(E) together with the carbon to which they are attachedform a substituted or unsubstituted cycloalkyl (such as a C₃-C₆cycloalkyl) or a substituted or unsubstituted heterocyclic (such as a 3-to 15-membered heterocyclic ring);

or R^(D) and R^(Z) together with the carbon and the NC(O) to which theyare attached form a substituted or unsubstituted lactam;

each of R^(F), R^(G) and R^(H) is independently selected from absent, H,D, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkyl, substituted or unsubstituted—C₆-C₁₀ aryl, substituted or unsubstituted 5- to 10-membered heteroaryl,substituted or unsubstituted —CH₂—C₅-C₁₀ aryl, and substituted orunsubstituted —CH₂—C₅-C₁₀ heteroaryl; or alternatively, two or three ofR^(F), R^(G) and R^(H) together with the N⁺ to which they are attachedform an optionally substituted heterocyclyl (such as a 3- to 15-memberedheterocyclic ring) having, zero, one or more heteroatoms in addition tothe N⁺, including, but not limited to, an optionally substitutedheteroaryl ring;

or two or three of R^(D), R^(E), R^(F), R^(G) and R^(H) together withthe N⁺ form an optionally substituted heterocyclic ring having, zero,one or more heteroatoms in addition to the N⁺, including but not limitedto, a heteroaryl ring; for example, two of R^(E), R^(F), and R^(G) aretaken together with the N⁺ to form a heterocyclic ring having, zero, oneor more heteroatoms in addition to the N⁺.

The invention further relates to derivatives of sodium channel blockercompounds comprising dimethyl anilide (for example, a caine compound)wherein the ortho methyl of the sodium channel blocker compound isreplaced by an ester. Examples of sodium channel blocker compoundsinclude, but are not limited to, lidocaine, bupivacaine, mepivacaine,etidocaine, prilocaine, tocainide, ropivacaine, proparacaine, allocaine,encainide, procainamide, metoclopramide, flecainide, tetracaine,benzocaine, oxybuprocaine, butambine, propoxycaine, dyclonine,pramocaine, chloroprocaine, proparacaine, piperocaine, hexylcaine,naepaine, cyclomethylcaine, and dibucaine, articaine, mexiletine,bupropion, ambroxol, procaine, tolperinone, and substituted derivativesthereof.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE illustrates the voltage protocol used in the Whole Cell PatchClamp Protocol.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds represented by Formula (I) asdescribed herein, as well as pharmaceutically acceptable salts,stereoisomers, solvates, hydrates or combinations thereof. The inventionalso provides compositions comprising compounds having Formula (I) orpharmaceutically acceptable salts thereof, for example, compositionscomprising an effective amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient. The compositions of the invention may furthercomprise compounds of the invention and a biologically active agent. Thecompositions described herein can be formulated for oral, intravenous,intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal,sublingual, nasal, inhalation, vaginal, intrathecal, epidural, or ocularadministration.

The invention further provides methods for treating pain, itch, or aneurogenic inflammatory disorder in a patient, including administeringto the patient an effective amount of a compound described herein or acomposition comprising an effective amount of a compound having Formula(I), wherein the compound inhibits one or more voltage-gated ionchannels present in nociceptors and/or cough receptors and/orpruriceptors when exposed or applied to the internal face of thechannels but does not substantially inhibit the channels when applied tothe external face of the channels, and wherein the compound is capableof entering nociceptors, cough receptors or pruriceptors through a largepore channel when the channel is activated and inhibiting one or morevoltage-gated ion channels present in the nociceptors cough receptors orpruriceptors.

In certain embodiments, the large pore channel is a transient receptorpotential ion channel (TRP channel). In other embodiments, the TRPchannel is activated by an exogenous or endogenous agonist. In yet otherembodiments, the large pore channel is TRPA1, TRPV1-4, TRPM8, ASIC orP2X. In particular embodiments, the compound is capable of enteringnociceptors, cough receptors or pruriceptors through the TRPA1 TRPV1-4,TRPM8, ASIC or P2X receptor/channel when the receptor/channel isactivated. In yet other embodiments, the compound inhibits voltage-gatedsodium channels. In yet other embodiments, the type of pain treated bythe methods, compositions, and kits of the invention is selected fromthe group consisting of neuropathic pain, inflammatory pain, nociceptivepain, pain due to infections, and procedural pain, or wherein theneurogenic inflammatory disorder is selected from the group consistingof allergic inflammation, asthma, chronic cough, conjunctivitis,rhinitis, psoriasis, inflammatory bowel disease, interstitial cystitis,and atopic dermatitis.

We have identified compounds having Formula (I)

that are capable of passing through open large pore channels that areexpressed on nociceptors and/or cough receptors and/or pruriceptors butnot on motor neurons. Because the ion channel blocking compounds of thepresent invention are positively charged, they are notmembrane-permeable and thus cannot enter cells that do not express largepore channels. Since large pore channels are often more active in tissueconditions associated with pain (such as inflammation) due to release ofendogenous ligands or activation by thermal stimuli, the ion channelblocker of the invention can be used alone to selectively targetactivated nociceptors in order to effectively treat (e.g., eliminate oralleviate) pain, cough, itch, or neurogenic inflammation. The ionchannel blockers of the invention can also be used in combination withone or more exogenous large pore channel agonists to selectively targetnociceptors in order to effectively treat (e.g., eliminate or alleviate)pain, itch, or neurogenic inflammation.

Voltage-dependent ion channels in pain-sensing neurons are currently ofgreat interest in developing drugs to treat pain. Blockingvoltage-dependent sodium channels in pain-sensing neurons can block painsignals by interrupting initiation and transmission of the actionpotential. Moreover, blocking voltage-dependent sodium channels innociceptors can reduce or eliminate neurogenic inflammation bypreventing activation of nociceptor peripheral terminals and the releasethereof pro-inflammatory chemicals.

Heretofore, a limitation in treating with molecules that block sodiumchannels or calcium channels is that the vast majority of suchexternally-applied molecules are hydrophobic and can pass throughmembranes. Because of this, they will enter all cells and thus have noselectivity for affecting only nociceptors.

The inhibitors of the present invention are membrane-impermeable and areonly effective when present inside the nociceptor cell, and thus mustpass through the cell membrane via a channel or receptor, such as largepore channels (e.g., TRPAV1-4, TRPA1, TRPM8, ASIC and P2X(2/3)), inorder to produce an effect. Under normal circumstances, most large porechannels in nociceptors are not active but require a noxious thermal,mechanical, or chemical stimulus to activate them. For example, TRPchannels in nociceptors can be activated by an exogenous TRP ligand(i.e. TRP agonist) such as capsaicin, which opens the TRPV1 channel.Thus, one approach to selectively targeting nociceptors is toco-administer the membrane-impermeable ion channel inhibitor with anexogenous TRP ligand that permits passage of the inhibitor through theTRP channel into the cell. In addition to capsaicin, the exogenous TRPligand can also be another capsaicinoid, mustard oil, or lidocaine. Inanother example, TRP channels may be active in response to exogenousirritant activators such as inhaled acrolein from smoke or chemicalwarfare agents such as tear gas.

Under certain circumstances, large pore channels can be activated in theabsence of exogenous large pore channel agonists/ligands by endogenousinflammatory activators that are generated by tissue damage, infection,autoimmunity, atopy, ischemia, hypoxia, cellular stress, immune cellactivation, immune mediator production, and oxidative stress. Under suchconditions, endogenous molecules (e.g., protons, lipids, and reactiveoxygen species) can activate large pore channels expressed onnociceptors, allowing membrane-impermeable, voltage-gated ion channelblockers to gain access to the inside of the nociceptor through theendogenously-activated large pore channels. Endogenous inflammatoryactivators of large pore channels include, for example, prostaglandins,nitric oxide (NO), peroxide (H₂O₂), cysteine-reactive inflammatorymediators like 4-hydroxynonenal, endogenous alkenyl aldehydes,endocannabinoids, and immune mediators (e.g., interleukin 1 (IL-1),nerve growth factor (NGF), and bradykinin, whose receptors are coupledto large pore channels).

Definitions

As used herein, the words “a” and “an” are meant to include one or moreunless otherwise specified.

By “biologically active” is meant that a molecule, including biologicalmolecules, such as nucleic acids, peptides, polypeptides, proteins,exerts a biological, physical, or chemical effect on a protein, enzyme,receptor, ligand, antigen, itself or other molecule. For example, a“biologically active” molecule may possess, e.g., enzymatic activity,protein binding activity, or pharmacological activities.

Biologically active agents that can be used in the methods and kitsdescribed herein include, without limitation, TRP1A receptor agonists,TRPV1-4 receptor agonists, ASIC agonists, TRPM8 agonists, P2X receptoragonists, NSAIDs, glucocorticoids, narcotics, anti-proliferative andimmune modulatory agents, an antibody or antibody fragment, anantibiotic, a polynucleotide, a polypeptide, a protein, an anti-canceragent, a growth factor, and a vaccine.

By “inflammation” is meant any types of inflammation, such those causedby the immune system (immune-mediated inflammation) and by the nervoussystem (neurogenic inflammation), and any symptom of inflammation,including redness, heat, swelling, pain, and/or loss of function.

By “neurogenic inflammation” is meant any type of inflammation mediatedor contributed to by neurons (e.g. nociceptors) or any other componentof the central or peripheral nervous system.

The term “pain” is used herein in the broadest sense and refers to alltypes of pain, including acute and chronic pain, such as nociceptivepain, e.g. somatic pain and visceral pain; inflammatory pain,dysfunctional pain, idiopathic pain, neuropathic pain, e.g., centrallygenerated pain and peripherally generated pain, migraine, and cancerpain.

The term “nociceptive pain” is used to include all pain caused bynoxious stimuli that threaten to or actually injure body tissues,including, without limitation, by a cut, bruise, bone fracture, crushinjury, burn, and the like. Pain receptors for tissue injury(nociceptors) are located mostly in the skin, musculoskeletal system, orinternal organs.

The term “somatic pain” is used to refer to pain arising from bone,joint, muscle, skin, or connective tissue. This type of pain istypically well localized.

The term “visceral pain” is used herein to refer to pain arising fromvisceral organs, such as the respiratory, gastrointestinal tract andpancreas, the urinary tract and reproductive organs. Visceral painincludes pain caused by tumor involvement of the organ capsule. Anothertype of visceral pain, which is typically caused by obstruction ofhollow viscus, is characterized by intermittent cramping and poorlylocalized pain. Visceral pain may be associated with inflammation as incystitis or reflux esophagitis.

The term “inflammatory pain” includes pain associates with activeinflammation that may be caused by trauma, surgery, infection andautoimmune diseases.

The term “neuropathic pain” is used herein to refer to pain originatingfrom abnormal processing of sensory input by the peripheral or centralnervous system consequent on a lesion to these systems.

The term “procedural pain” refers to pain arising from a medical, dentalor surgical procedure wherein the procedure is usually planned orassociated with acute trauma.

The term “itch” is used herein in the broadest sense and refers to alltypes of itching and stinging sensations localized and generalized,acute intermittent and persistent. The itch may be idiopathic, allergic,metabolic, infectious, drug-induced, due to liver, kidney disease, orcancer. “Pruritus” is severe itching.

By “patient” is meant any animal. In one embodiment, the patient is ahuman. Other animals that can be treated using the methods,compositions, and kits of the invention include, but are not limited to,non-human primates (e.g., monkeys, gorillas, chimpanzees), domesticatedanimals (e.g., horses, pigs, goats, rabbits, sheep, cattle, llamas), andcompanion animals (e.g., guinea pigs, rats, mice, lizards, snakes, dogs,cats, fish, hamsters, and birds).

Compounds useful in the invention include, but are not limited to, thosedescribed herein in any of their pharmaceutically acceptable forms,including isomers such as diastereomers and enantiomers, salts, esters,amides, thioesters, solvates, and polymorphs thereof, as well as racemicmixtures and pure isomers of the compounds described herein. The term“pharmaceutically acceptable anion” as used herein, refers to theconjugate base of a pharmaceutically acceptable acid. Such acids aredescribed in Stahl, P. H. and Wermuth, C. G. (eds.), Handbook ofPharmaceutical Salts: Properties, Selection and Use, Wiley VCH (2008).Pharmaceutically acceptable acids include, but are not limited to,acetic acid, dichloroacetic acid, adipic acid, alginic acid, L-ascorbicacid, L-aspartic acid, benzenesulfonic acid, 4-acetamidobenzoic acid,benzoic acid, p-bromophenylsulfonic acid, (+)-camphoric acid,(+)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid,carbonic acid, cinnamic acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonicacid, sulfuric acid, boric acid, citric acid, formic acid, fumaric acid,galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid,D-glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrochloric acid,hydrobromic acid, hydroiodic acid, isobutyric acid, DL-lactic acid,lactobionic acid, lauric acid, maleic acid, (−)-L-malic acid, malonicacid, DL-mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonicacid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, phosphoric acid, propionic acid, (−)-L-pyroglutamic acid,salicyclic acid, 4-aminosalicyclic acid, sebacic acid, stearic acid,succinic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonicacid, and undecylenic acid. Pharmaceutically acceptable anions includethe conjugate base of any the acids set forth above.

The term “pharmaceutically acceptable salt” represents those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. The salts can beprepared in situ during the final isolation and purification of thecompounds of the invention, or separately by reacting the free basefunction with a suitable organic acid. Representative acid additionsalts include, but are not limited to, acetate, adipate, alginate,ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, isethionate,lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate,nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,toluenesulfonate, undecanoate, valerate salts, and the like.

In the generic descriptions of compounds of this invention, the numberof atoms of a particular type in a substituent group is generally givenas a range, e.g., an alkyl group containing from 1 to 4 carbon atoms orC₁-C₄ alkyl. Reference to such a range is intended to include specificreferences to groups having each of the integer number of atoms withinthe specified range. For example, an alkyl group from 1 to 4 carbonatoms includes each of C₁, C₂, C₃, and C₄. Other numbers of atoms andother types of atoms may be indicated in a similar manner.

“D” is deuterium.

As used herein, the terms “alkyl” and the prefix “alk-” are inclusive ofboth straight chain and branched chain groups and of cyclic groups,i.e., cycloalkyl. Cyclic groups can be monocyclic or polycyclic, andpreferably have from 3 to 6 ring carbon atoms, inclusive. Exemplarycyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl groups. By “C_(1-*) alkyl” is meant a branched, unbranched orcyclic hydrocarbon group having from 1 to * carbon atoms, where * is aninteger, such as 2, 3, 4, 5, 6, 7, 8, 10, 12, or more. An alkyl groupmay be substituted or unsubstituted. Exemplary substituents includealkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br orI), hydroxyl, fluoroalkyl, perfluoralkyl, oxo, amino, alkylamino,disubstituted amino, quaternary amino, amido, ester, alkylcarboxy,alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl,alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonato,phosphinato, acylamino (including alkylcarbonylamino, arylcarbonylamino,carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety. In certain aspects,the alkyl is a C₁-C₆ alkyl. C₁₋₆ alkyls include, without limitation,methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl and cyclohexyl. Another specific example of asubstituted alkyl is:

Another example of a substituted alkyl is a heteroalkyl. By“heteroalkyl” is meant a branched or unbranched alkyl, cycloalkyl,alkenyl, or alkynyl group having from 1 to 7 or more carbon atoms inaddition to 1, 2, 3 or 4 heteroatoms independently selected from thegroup consisting of N, O, S, and P. Heteroalkyls can include, withoutlimitation, tertiary amines, secondary amines, ethers, thioethers,amides, thioamides, carbamates, thiocarbamates, hydrazones, imines,phosphodiesters, phosphoramidates, sulfonamides, and disulfides. Aheteroalkyl may optionally include monocyclic, bicyclic, or tricyclicrings, in which each ring desirably has three to six members. Theheteroalkyl group may be substituted or unsubstituted. Exemplarysubstituents include alkyl, alkoxy, aryloxy, sulfhydryl, alkylthio,arylthio, halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoralkyl,oxo, amino, alkylamino, disubstituted amino, quaternary amino, amido,ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl,alkylthiocarbonyl, phosphate, phosphonato, phosphinato, acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl, andureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety. Examples of C₁₋₇heteroalkyls include, without limitation, methoxymethyl and ethoxyethyl.

An alkenyl is a branched or unbranched hydrocarbon group containing oneor more double bonds. For example, by “C₂₋₆ alkenyl” or “C₂-C₆ alkenyl”is meant a branched or unbranched hydrocarbon group containing one ormore double bonds and having from 2 to 6 carbon atoms. An alkenyl mayoptionally include monocyclic or polycyclic rings, in which each ringdesirably has from three to six members. The alkenyl group may besubstituted or unsubstituted. Exemplary substituents include thosedescribed above for alkyl, and specifically include alkoxy, aryloxy,sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl,perfluoralkyl, amino, alkylamino, disubstituted amino, quaternary amino,alkylcarboxy, and carboxyl groups. C₂₋₆ alkenyls include, withoutlimitation, vinyl, allyl, 2-cyclopropyl-1-ethenyl, 1-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, and2-methyl-2-propenyl.

An alkynyl is a branched or unbranched hydrocarbon group containing oneor more triple bonds. For example, by “C₂₋₆ alkynyl” or “C₂-C₆ alkynyl”is meant a branched or unbranched hydrocarbon group containing one ormore triple bonds and having from 2 to 6 carbon atoms. An alkynyl mayoptionally include monocyclic, bicyclic, or tricyclic rings, in whicheach ring desirably has five or six members. The alkynyl group may besubstituted or unsubstituted. Exemplary substituents those describedabove for alkyl, and specifically include alkoxy, aryloxy, sulfhydryl,alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino,alkylamino, disubstituted amino, quaternary amino, alkylcarboxy, andcarboxyl groups. C₂₋₆ alkynyls include, without limitation, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

By “heterocyclyl,” “heterocyclic,” or “heterocycloalkyl” is meant astable monocyclic or a polycyclic (including a bicyclic or a tricyclic)heterocyclic ring which is saturated, partially unsaturated orunsaturated (including heteroaryl or aromatic), and which consists of 2or more carbon atoms and 1, 2, 3 4 or more heteroatoms independentlyselected from P, N, O, and S and including any bicyclic or polycyclicgroup in which any of the above-defined heterocyclic rings is fused to abenzene ring, heteroaryl, cycloalkyl or heterocycloalkyl. In certainaspects, the heterocyclyl is a 3- to 15-membered ring system, a 3- to12-membered ring system, or a 3- to 9-membered ring system. Theheterocyclyl (including heteroaryl groups) may be substituted orunsubstituted. Exemplary substituents include substituted orunsubstituted alkyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio,halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoralkyl, oxo,amino, alkylamino, disubstituted amino, quaternary amino, amido, ester,alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy,carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate,phosphonato, phosphinato, acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,aryl, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.Nitrogen and sulfur heteroatoms may optionally be oxidized. Theheterocyclic ring may be covalently attached via a heteroatom or carbonatom which results in a stable structure, e.g., an imidazolinyl ring maybe linked at either of the ring-carbon atom positions or at the nitrogenatom. A nitrogen or phosphorus atom in the heterocycle can bequaternized. Preferably when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother. Heterocycles include, without limitation, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, xanthenyl, β-lactam, γ-lactam and δ-lactam. Preferred 5to 10 membered heterocycles include, but are not limited to, pyridinyl,pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl,benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl,isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl,benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 memberedheterocycles include, without limitation, pyridinyl, quinolinyl,pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,and tetrazolyl. Preferred substituents include phenyl, methyl, ethyl,propyl, butyl, oxo, chloro, bromo, fluoro and iodo.

By “aryl” is meant an aromatic group having a ring system comprised ofcarbon atoms with conjugated π electrons (e.g., phenyl). A “C₆-C₁₂ aryl”or “C₆-C₁₀ aryl” is an aryl group has from 6 to 12 carbon atoms or 6 to10 carbon atoms, respectively. Aryl groups may optionally includemonocyclic, bicyclic, or tricyclic rings, in which each ring desirablyhas five or six members. Ring systems can be fused (e.g., naphthyl) ornot (biphenyl). The aryl group may be substituted or unsubstituted.Exemplary substituents include substituted or unsubstituted alkyl,alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br orI), hydroxyl, fluoroalkyl, perfluoralkyl, oxo, amino, alkylamino,disubstituted amino, quaternary amino, amido, ester, alkylcarboxy,alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl,alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonato,phosphinato, acylamino (including alkylcarbonylamino, arylcarbonylamino,carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

By “aralkyl” is meant a substituted or unsubstituted alkyl that issubstituted by a substituted or unsubstituted aryl (including, forexample, (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl)). By“heteroaralkyl” is meant a substituted or unsubstituted alkyl that issubstituted by or heteroaryl group.

By “halide” or “halogen” is meant bromine, chlorine, iodine, orfluorine.

By “fluoroalkyl” is meant an alkyl group that is substituted with one ormore fluorine atoms, such as a perfluoroalkyl group. Trifluoromethyl,difluoromethyl, fluoromethyl and heptafluoroethyl are examples.

By “alkoxy” is meant a chemical moiety with the formula —O—R, wherein Ris substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, or substituted or unsubstituted alkynyl.

By “alkylcarboxy” is meant a chemical moiety with the formula —(R)—COOH,wherein R is selected from alkyl (e.g. C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇alkynyl), heterocyclyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, orheteroalkyl, each optionally substituted.

By “charged moiety” is meant a moiety which gains a proton atphysiological pH thereby becoming positively charged (e.g., ammonium,guanidinium, or amidinium) or a moiety that includes a net formalpositive charge without protonation (e.g., quaternary ammonium). Thecharged moiety may be either permanently charged or transiently charged.

By “therapeutically effective amount” or “effective amount” is meant anamount sufficient to produce a desired result, for example, thereduction or elimination of pain, itch, or neurogenic inflammation in apatient (e.g., a human) suffering from a condition, disease, or illnessthat is caused wholly or in part by neurogenic inflammation (e.g.asthma, arthritis, colitis, contact dermatitis, diabetes, eczema,cystitis, chronic refractory cough, post-viral cough, gastritis,migraine headache, psoriasis, rhinitis, rosacea, or sunburn).

“Solvates” means solvent addition forms that contain eitherstoichiometric or nonstoichiometric amounts of solvent, includinghydrates.

The compounds of the present invention, including salts of thecompounds, can exist in unsolvated forms as well as solvated forms,including hydrated forms and unhydrated forms. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of the present invention. Nonlimiting examples of hydrates includemonohydrates, dihydrates, hemihydrates, etc. In certain aspects, thecompound is a hemihydrate. Nonlimiting examples of solvates includeethanol solvates, acetone solvates, etc.

The compounds of the invention may exist in multiple crystalline(polymorphs) or amorphous forms. In general, any physical forms can beused in the present invention and are intended to be within the scope ofthe invention. Stable crystalline forms are preferred.

The invention further relates to derivatives of sodium channel blockercompounds comprising a dimethyl anilide group (for example, a cainecompound) wherein an ortho methyl of the sodium channel blocker isreplaced by an ester group. Examples of caine compounds include, but arenot limited to, lidocaine, bupivacaine, mepivacaine, etidocaine,prilocaine, tocainide, ropivacaine, proparacaine, allocain, encainide,procainamide, metoclopramide, flecainide, tetracaine, benzocaine,oxybuprocaine, butambine, propoxycaine, dyclonine, pramocaine,chloroprocaine, proparacaine, piperocaine, hexylcaine, naepaine,cyclomethylcaine, and bipucaine, and substituted derivatives thereof.

Compounds that can be used in the compositions, kits, and methods of theinvention include compounds having Formula (I), or a pharmaceuticallyacceptable salt:

wherein

Y⁻ is a pharmaceutically acceptable anion and the other variables are asdefined herein. Preferred embodiments of the variables are alsoprovided. It is intended that each preferred selection can be combinedwith one or other preferred selections (combining between two or morelist) as though this specification offered each and every possiblecombination and permutation in the alternative.

R^(A) is preferably COOMe (methoxycarbonyl) or COOEt (ethoxycarbonyl),

R^(B) is preferably H, D, substituted or unsubstituted alkyl; morepreferably methyl or ethyl, such as methyl;

R^(C) is preferably selected from H, D, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, OR^(I), CN, NR^(J)R^(K), NR^(L)C(O)R^(M),S(O)R^(N), S(O)₂R^(N), SO₂R^(O)R^(P), SO₂NR^(Q)R^(R), SO₃R^(S),CO₂R^(T), C(O)R^(U), and C(O)NR^(V)R^(W); and wherein each of R^(I),R^(J), R^(K), R^(L), R^(M), R^(N), R^(O), R^(P), R^(Q), R^(R), R^(S),R^(T), R^(U), R^(V), and R^(W) is independently selected from H, D,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, and substituted or unsubstituted alkynyl.

R^(C) is preferably para-substituted (4-substituted).

In additional preferred embodiments, R^(B) is CH₃ and R^(C) is hydrogen.

X¹ can be selected from —CR^(X)R^(Y), —NR^(Z)C(O)—,—NR^(Z)C(O)CR^(X)R^(Y)—, —OC(O)—, —SC(O)—, —C(O)NR^(1A)—, —C(O)O—,—C(O)—, —(O)CS—, —NR^(1A)S(O)—, —S(O)NR^(1A)—, —NR^(1A)C(O)NR^(1A)—,—S(O)— and —S(O)₂—; and each of R^(X), R^(Y), R^(Z), and R^(1A) isindependently selected from H, D, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, and substituted or unsubstitutedalkynyl. In a preferred embodiment, X¹ is —NR^(Z)C(O)—. In additionalpreferred embodiments, R^(Z) is hydrogen. In yet an additional preferredembodiment, X¹ is —NR^(Z)C(O)— and R^(Z) is hydrogen. In certainpreferred embodiments, X¹ is —NHC(O)—.

Each of R^(D) and R^(E) is independently selected from H, D, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, and substituted or unsubstitutedcycloalkyl; or R^(D) and R^(E) together form a substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstitutedheterocyclic. R^(D) and R^(E) can both be hydrogen. R^(D) can behydrogen and R^(E) can be an alkyl, for example, a C₁-C₆ alkyl or aC₁-C₄ alkyl including, but not limited to, methyl, ethyl, propyl andbutyl. R^(D) and R^(E) can be taken together with the carbon to whichthey are attached to form a C₃-C₆ cycloalkyl including, but not limitedto, cyclopropyl or cyclobutyl. R^(D) can be hydrogen and R^(E) can betaken together with R^(F) to form a heterocyclic ring, preferably having5 or 6 ring atoms. R^(D) can be hydrogen and R^(Z) can be taken togetherwith R^(F) to form a lactam ring, preferably having 5 or 6 ring atoms.

Each of R^(F), R^(G) and R^(H) is independently selected from H, D,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted —C₆-C₁₀ aryl, substituted or unsubstituted5- to 10-membered heteroaryl, substituted or unsubstituted aralkyl(e.g., —CH₂—C₆-C₁₀ aryl) and a substituted or unsubstitutedheteroarylalkyl (e.g., —CH₂-heteroaryl where the heteroaryl ispreferably a 5- to 10-membered heteroaryl). For example, each of R^(F),R^(G) and R^(H) are the same or different and is a substituted orunsubstituted alkyl, such as methyl, ethyl, n-propyl, and n-butyl, forexample, each of R^(F), R^(G) and R^(H) can be ethyl. For example, one,two or three of R^(F), R^(G) and R^(H) is independently an aryl group(preferably, phenyl), aralkyl (preferably, benzyl), or a heteroaralkyl.For example, R^(H) is a substituted or unsubstituted aryl (preferably,phenyl) or aralkyl (preferably, benzyl), and R^(F) and R^(G) are thesame or different and are each independently a substituted orunsubstituted alkyl, such as a substituted or unsubstituted C₁-C₆ alkylor a substituted or unsubstituted C₁-C₄ alkyl, including, for example,methyl, ethyl, n-propyl, and n-butyl; preferably ethyl. Or, at least oneof R^(F), R^(G) and R^(H) is

As will be understood, wherein one of R^(F), R^(G), and R^(H) is theradical above, then the compound of Formula (I) is a dimer; for example,a symmetric or asymmetric dimer (around the N⁺ atom). For example, R^(E)and R^(H) can be H, R^(F) and R^(G) can be the same or differentsubstituted or unsubstituted alkyl, such as methyl or ethyl, and R^(H)is:

In certain aspects, two or three of R^(F), R^(G) and R^(H) together withthe N⁺ to which they are attached form an optionally substitutedheterocyclic ring having, zero, one, or more heteroatoms in addition tothe N⁺. In certain preferred aspects, the heterocyclyl has 5, 6, or 7ring atoms (in other words, is 5-, 6-, or 7-membered). In furtherpreferred embodiments, the optionally substituted heterocyclic is anoptionally substituted heteroaryl, such as pyridinium. In yet additionalpreferred embodiments, two of R^(F), R^(G) and R^(H) together with N⁺ towhich they are attached form an optionally substituted heterocyclic ringhaving, zero, one, or more heteroatoms in addition to the N⁺. Inadditional preferred aspects, R^(F) and R^(G) are taken together withthe N⁺ to which they are attached to form a heterocyclyl having 5, 6 or7 ring atoms, and R^(H) is an aralkyl or a heteroaralkyl. In yet furtherpreferred aspects, R^(F) and R^(G) together with the N⁺ to which theyare attached form an optionally substituted heterocyclic ring having,zero, one, or more heteroatoms in addition to the N⁺, and R^(H) is—CH₂—Z; wherein Z is a substituted or unsubstituted aryl or asubstituted or unsubstituted heteroaryl; preferably, Z is selected fromthe group consisting of unsubstituted phenyl; phenyl substituted by aC₁-C₄ alkyl (for example, methyl, ethyl, n-propyl, and n-butyl), halogen(for example, fluoro or chloro), methoxy, ethoxy, and cyano; substitutedor unsubstituted heteroaryl. Preferably, Z is selected from Tables 1, 2,and 3 below.

Two or three of R^(D), R^(E), R^(F), R^(G) and R^(H) can also be takentogether with the N⁺ to form an optionally substituted heterocyclic ringhaving, zero, one, or more heteroatoms in addition to the N⁺. Suchheterocyclic rings include, but are not limited to, heteroaryl rings.Preferably, the heterocyclic ring has 5, 6, or 7 ring members, forexample, the heterocyclyl ring can have 4, 5, or 6 carbons. Preferably,two of R^(E), R^(F), and R^(G) are taken together with the N⁺ form aheterocyclic ring. In yet additional preferred embodiments, two ofR^(E), R^(F), and R^(G) are taken together with the N⁺ form aheterocyclic ring and R^(D) is hydrogen. In yet further preferredembodiments, two of R^(E), R^(F), and R^(G) are taken together with theN⁺ to form a heterocyclic ring, R^(D) is optionally hydrogen, and R^(G)and R^(H) are alkyl, such as methyl, ethyl, propyl and butyl. In yetfurther embodiments, two of R^(E), R^(F), and R^(G) are taken togetherwith the N⁺ to form a heterocyclic ring, R^(D) is optionally hydrogen,and R^(G) and/or R^(H) are aralkyl, such as benzyl, or heteroaralkyl.

In another embodiment, each of R^(F), R^(G) and R^(H) is independentlyselected from phenyl, CH₃, CH₂CH₃, (CH₂)₂CH₃, (CH₂)₃CH₃, and (CH₂)₄CH₃.In another embodiment, each of R^(F), R^(G) and R^(H) is the same andselected from phenyl, CH₃, CH₂CH₃, (CH₂)₂CH₃, (CH₂)₃CH₃, and (CH₂)₄CH₃.

Y⁻ is typically a pharmaceutically acceptable ion. For example, Y⁻ canbe a halide anion, a carboxylate, or a sulfonate. Y⁻ can, for example,be a halide ion, a substituted or unsubstituted alkylsulfonate, asubstituted or unsubstituted arylsulfonate, a substituted orunsubstituted alkyl or aliphatic carboxylate, a substituted orunsubstituted aryl carboxylate, or a substituted or unsubstitutedheterocyclyl carboxylate.

Y⁻ can be trifluoroacetate, sulfate, phosphate, acetate, fumarate,formate, carbonate, maleate, citrate, pyruvate, succinate, oxalate, asulfonate, (for example, methanesulfonate, trifluoromethanesulfonate,toluenesulfonate such as p-toluenesulfonate, benzenesulfonate,ethanesulfonate, camphorsulfonate, 2-mesitylenesulfonate, ornaphthalenesulfonate such as 2-naphthalenesulfonate), bisulfate,malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate,adipate, formate, glycolate, L-lactate, D-lactate, aspartate, malate,L-tartrate, D-tartrate, stearate, 2-furoate, 3-furoate, napadisylate(naphthalene-1,5-disulfonate or naphthalene-1-(sulfonicacid)-5-sulfonate), edisylate (ethane-1,2-disulfonate orethane-1-(sulfonic acid)-2-sulfonate), isethionate(2-hydroxyethylsulfonate), D-mandelate, L-mandelate, propionate,tartarate, phthalate, hydrochlorate, hydrobromate, and nitrate. In oneembodiment, Y⁻ is a halide anion.

In a preferred embodiment, the Y⁻ anion is selected from the halide ionsbromide, chloride, or iodide.

In certain preferred embodiments, the present invention relates tocompounds of Formula (I), or a pharmaceutically acceptable salt thereof,wherein R^(H) is an optionally substituted —CH₂-aryl or optionallysubstituted —CH₂-heteroaryl selected from one of the following:

In preferred embodiments, R^(F) and R^(G) together with the N⁺ to whichthey are attached form a five, six, seven, or eight memberedheterocyclic ring, each optionally substituted, resulting in a compoundof Formula (Ia):

Wherein each variable is as defined above, including preferred oralternative embodiments, n is 1, 2, 3, 4 or 5; and R^(1B) is H or asubstituent, such as H, D, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, OR^(1I), CN, NR^(1J)R^(1K),NR^(1L)C(O)R^(1M), S(O)R^(1N), S(O)₂R^(1N), SO₂R^(1O)R^(1P),SO₂NR^(1Q)R^(1R), SO₃R^(1S), CO₂R^(1T), C(O)R^(1U), andC(O)NR^(1V)R^(1W); and wherein each of R^(1I), R^(1J), R^(1K), R^(1L),R^(1M), R^(1N), R^(1O), R^(1P), R^(1Q), R^(1R), R^(1S), R^(1T), R^(1U),R^(1V), and R^(1W) is independently selected from H, D, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl. R^(1J) and R^(1K) orR^(1V) and R^(1W) or R^(1Q) and R^(1R) can also be taken together withthe nitrogen to which they are attached to form a substituted orunsubstituted 5, 6, 7, or 8 membered ring.

In preferred embodiments, R^(F) and R^(G) together with the N⁺ to whichthey are attached form a five, six, seven, or eight-memberednitrogen-containing heterocyclic ring, including, but not limited to:

each optionally substituted. Preferred substituents include phenyl,CO₂R^(IT) and C(O)NR^(1V)R^(1W).

Preferred compounds can be represented by Formula (Ib):

Wherein each variable is as defined above, including preferred oralternative embodiments.

More preferably, the compounds have the formula:

Wherein each variable is as defined above, including preferred oralternative embodiments and R^(1B) is H or a substituent, such as H, D,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, OR^(1I), CN, NR^(1J)R^(1K), NR^(1L)C(O)R^(1M),S(O)R^(IN), S(O)₂R^(IN), SO₂R^(1O)R^(1P), SO₂NR^(1Q)R^(1R), SO₃R^(1S),CO₂R^(1T), C(O)R^(1U), and C(O)NR^(1V)R^(1W); and wherein each ofR^(1I), R^(1J), R^(1K), R^(1L), R^(1M), R^(1N), R^(1O), R^(1P), R^(1Q),R^(1R), R^(1S), R^(1T), R^(1U), R^(1V), and R^(1W) is independentlyselected from H, D, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl. R^(1J) and R^(1K) or R^(1V) and R^(1W) or R^(1Q) andR^(1R) can also be taken together with the nitrogen to which they areattached to form a substituted or unsubstituted 5, 6, 7, or 8 memberedring. R^(1B) is preferably a substituted or unsubstituted aryl orheteroaryl, e.g., phenyl.

Each preferred embodiment described herein can be taken in combinationwith one, any or all other preferred embodiments, as though presentedhere in every permutation.

In certain aspects, the compound is selected from those shown below, ora pharmaceutically acceptable salt thereof, wherein Y⁻ is apharmaceutically acceptable anion:

TABLE 1 Representative Z Structures No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 2 Representative Z Structures No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

TABLE 3 Representative Z Structures No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

Additional representative compounds include those in the following tablewherein R is either COOMe or COOEt:

Compositions of the invention can comprise racemic mixtures, pureenantiomers, or an excess of one enantiomer over the other. For example,a composition can comprise an enantiomeric excess of at least 5, 10, 20,30, 40, 50, 60, 70, 80 or 90%. In one embodiment, the enantiomericexcess is at least 95%.

The compounds of the invention include all enantiomers which may bedefined, in terms of absolute stereochemistry, as (R)- or (S)-, as wellas their racemic and optically pure forms, and is not limited to thosedescribed herein in any of their pharmaceutically acceptable forms,including enantiomers, salts, solvates, polymorphs, solvatomorphs,hydrates, anhydrous and other crystalline forms and combinationsthereof. Likewise, all tautomeric forms are intended to be included.

Preferably, a pharmaceutical composition comprises a compound of theinvention as an R enantiomer in substantially pure form; or, apharmaceutical composition comprises a compound of the invention as an Senantiomer in substantially pure form; or, a pharmaceutical compositioncomprises a compound of the invention as enantiomeric mixtures whichcontain an excess of the R enantiomer or an excess of the S enantiomer.It is particularly preferred that the pharmaceutical compositioncontains a compound of the invention which is a substantially pureoptical isomer. For the avoidance of doubt, a compound of the inventioncan, if desired, be used in the form of solvates.

Synthesis

Compounds having Formula (I) can be prepared using methods analogous tothe following general synthetic schemes:

and,

and

and,

Additional Biologically Active Agents and Exogenous Large Pore ChannelAgonists

As described above, the compound or composition of the invention can beadministered with a biologically active agent. For example, one or moreadditional biologically active agents, including those typically used totreat neurogenic inflammation, may be used in combination with acompound or composition of the invention described herein. Thebiologically active agents include, but are not limited to, TRP1Areceptor agonists, TRPV1-4 receptor agonists, TRPM8 agonists, ASICagonists, P2X receptor agonists, acetaminophen, NSAIDs, glucocorticoids,narcotics, tricyclic antidepressants, amine transporter inhibitors,anticonvulsants, anti-proliferative and immune modulatory agents, anantibody or antibody fragment, an antibiotic, a polynucleotide, apolypeptide, a protein, an anti-cancer agent, a growth factor, and avaccine.

TRPV1 agonists that can be employed in the methods, kits andcompositions of the invention include, but are not limited to, any thatactivates TRPV1 receptors on nociceptors and allows for entry of atleast one inhibitor of voltage-gated ion channels (for example, acompound of the invention). A suitable TRPV1 agonist is capsaicin oranother capsaicinoids, which are members of the vanilloid family ofmolecules. Naturally occurring capsaicinoids are capsaicin itself,dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin,homocapsaicin, and nonivamide. Other suitable capsaicinoids andcapsaicinoid analogs and derivatives for use in the compositions andmethods of the present invention include naturally occurring andsynthetic capsaicin derivatives and analogs including, e.g., vanilloids(e.g., N-vanillyl-alkanedienamides, N-vanillyl-alkanedienyls, andN-vanillyl-cis-monounsaturated alkenamides), capsiate, dihydrocapsiate,nordihydrocapsiate and other capsinoids, capsiconiate,dihydrocapsiconiate and other coniferyl esters, capsiconinoid,resiniferatoxin, tinyatoxin, civamide, N-phenylmethylalkenamidecapsaicin derivatives, olvanil,N-[(4-(2-aminoethoxy)-3-methoxyphenyl)methyl]-9Z-octa-decanamide,N-oleyl-homovanillamide, triprenyl phenols (e.g., scutigeral),gingerols, piperines, shogaols, guaiacol, eugenol, zingerone, nuvanil,NE-19550, NE-21610, and NE-28345. Additional capsaicinoids, theirstructures, and methods of their manufacture are described in U.S. Pat.Nos. 7,446,226 and 7,429,673, which are hereby incorporated byreference.

Additional suitable TRPV1 agonists include but are not limited toeugenol, arvanil (N-arachidonoylvanillamine), anandamide,2-aminoethoxydiphenyl borate (2APB), AM404, resiniferatoxin, phorbol12-phenylacetate 13-acetate 20-homovanillate (PPAHV), olvanil (NE19550), OLDA (N-oleoyldopamine), N-arachidonyldopamine (NADA),6′-iodoresiniferatoxin (6′-IRTX), C18 N-acylethanolamines, lipoxygenasederivatives such as 12-hydroperoxyeicosatetraenoic acid, inhibitorcysteine knot (ICK) peptides (vanillotoxins), piperine, MSK195(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide),JYL79(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-(4-hydroxy-3-methoxybenzyl)thiourea),hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 10-shogaol,oleylgingerol, oleylshogaol, and SU200(N-(4-tert-butylbenzyl)-N′-(4-hydroxy-3-methoxybenzyl)thiourea). Stillother TRPV1 agonists include amylocaine, articaine, benzocaine,bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine,dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine,hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine(oracaine), metabutoxycaine, piperocaine, prilocaine, procaine(novacaine), proparacaine, propoxycaine, risocaine, ropivacaine,tetracaine (amethocaine), and trimecaine.

Suitable TRPV2-4 agonists include, but are not limited to, are 2-APB,cannabinol, diphenylboronic anhydride, insulin-like growth factor 1,lysophosphatidylcholine, lysophosphatidylinositol, probenecid,Δ9-tetrahydrocannabinol, vanillin, eugenol, cinnamaldehyde, camphor,carvacrol, thymol, citral, farnesyl diphosphate, tetrahydrocannabivarin,incensole acetate, diphenylboronic anhydride, 6-tert-butyl-m-cresol,dihydrocarveocarveol, borneol, (−)-menthol, GSK1016790A, 4α-PDH,5,6-epoxyeicosatrienoic acid, 4α-PDD, bisandrographolide, citric acid,phorbol 12-myristate 13-acetate and RN1747.

Suitable TRPM8 agonists include, but are not limited to, are menthol,icilin, eucalyptus, linalool, geraniol, hydroxy-citronellal, WS-3,WS-23, Frescolat MGA, Frescolat ML, PMD 38, CPS125, Coolact P, M8-Ag,AITC, cryosim-3 and Cooling Agent 10.

Suitable ASIC agonists include, but are not limited to,chlorophenylguanidine hydrochloride, GMQ hydrochloride,tetrahydropapaveroline (THP), reticulin, polyamine agmatine,lysophosphatidylcholine, arachidonic acid and neuropeptide SF.

Other biologically active agents which can be employed in the methods,compositions, and kits of the invention include any that activates TRP1Areceptors on nociceptors or pruriceptors and allows for entry of atleast one inhibitor of voltage-gated ion channels. Suitable TRP1Aagonists include but are not limited to cinnamaldehyde,allyl-isothiocynanate (mustard oil), diallyl disulfide, icilin, cinnamonoil, wintergreen oil, clove oil, acrolein, hydroxy-alpha-sanshool,2-aminoethoxydiphenyl borate, 4-hydroxynonenal, methylp-hydroxybenzoate, and 3′-carbamoylbiphenyl-3-yl cyclohexylcarbamate(URB597).

P2X agonists that can be employed in the methods, compositions, and kitsof the invention include any that activates P2X receptors on nociceptorsor pruriceptors and allows for entry of at least one inhibitor ofvoltage-gated ion channels. Suitable P2X agonists include, but are notlimited to, ATP, α,β-methylene ATP 2-methylthio-ATP, 2′ and3′-O-(4-benzoylbenzoyl)-ATP, and ATP5′-O-(3-thiotriphosphate).

Other biologically active agents that can be used in combination withthe compounds of the invention include NSAIDs, glucocorticoids,narcotics, tricyclic antidepressants, amine transporter inhibitors,anticonvulsants, anti-proliferative and immune modulatory agents, anantibody or antibody fragment, an antibiotic, a polynucleotide, apolypeptide, a protein, an anti-cancer agent, a growth factor, and avaccine.

Non-steroidal anti-inflammatory drugs (NSAIDs) that can be administeredto a patient (e.g., a human) suffering from neurogenic inflammation incombination with a composition of the invention include, but are notlimited to, acetylsalicylic acid, amoxiprin, benorylate, benorilate,choline magnesium salicylate, diflunisal, ethenzamide, faislamine,methyl salicylate, magnesium salicylate, salicyl salicylate,salicylamide, diclofenac, aceclofenac, acemethacin, alclofenac,bromfenac, etodolac, indometacin, nabumetone, oxametacin, proglumetacin,sulindac, tolmetin, ibuprofen, alminoprofen, benoxaprofen, carprofen,dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen,flurbiprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen,naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid, mefenamicacid, flufenamic acid, meclofenamic acid, tolfenamic acid,phenylbutazone, ampyrone, azapropazone, clofezone, kebuzone, metamizole,mofebutazone, oxyphenbutazone, phenazone, sulfinpyrazone, piroxicam,droxicam, lornoxicam, meloxicam, tenoxicam, and the COX-2 inhibitorscelecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib,and pharmaceutically acceptable salts thereof.

Glucocorticoids that can be administered to a patient (e.g., a human)suffering from neurogenic inflammation in combination with a compositionof the invention include, but are not limited to, hydrocortisone,cortisone acetate, prednisone, prednisolone, methylprednisolone,dexamethasone, betamethasone, triamcinolone, beclometasone,fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, andpharmaceutically acceptable salts thereof.

Narcotics that can be administered to a patient (e.g., a human)suffering from neurogenic inflammation in combination with a compositionof the invention include, but are not limited, to tramadol, hydrocodone,oxycodone, morphine, and pharmaceutically acceptable salts thereof.

Antiproliferative and immune modulatory agents that can be administeredto a patient (e.g., a human) suffering from neurogenic inflammation incombination with a composition of the invention include, but are notlimited to, alkylating agents, platinum agents, antimetabolites,topoisomerase inhibitors, dihydrofolate reductase inhibitors, antitumorantibiotics, antimitotic agents, aromatase inhibitors, thymidylatesynthase inhibitors, DNA antagonists, farnesyltransferase inhibitors,pump inhibitors, histone acetyltransferase inhibitors, metalloproteinaseinhibitors, ribonucleoside reductase inhibitors, TNF-alpha agonists,TNF-alpha antagonists or scavengers, interleukin 1 (IL-1) antagonists orscavengers, endothelin A receptor antagonists, retinoic acid receptoragonists, hormonal agents, antihormonal agents, photodynamic agents, andtyrosine kinase inhibitors.

The biologically active agents can be administered prior to, concurrentwith, or following administration of a composition of the invention,using any formulation, dosing, or administration known in the art thatis therapeutically effective.

Formulation of Compositions

The administration of the compounds of the invention may be by anysuitable means that results in the reduction of perceived pain sensationat the target region. The compounds of the invention may be contained inany appropriate amount in any suitable carrier substance and aregenerally present in amounts totaling 1-99% by weight of the totalweight of the composition.

The composition may be provided in a dosage form that is suitable fororal, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous,subcutaneous, topical, transdermal, sublingual, nasal, vaginal,intrathecal, epidural, or ocular administration, or by injection,inhalation, or direct contact with the nasal or oral mucosa.

Thus, the composition may be in the form of, e.g., tablets, capsules,pills, powders, granulates, suspensions, emulsions, solutions, gelsincluding hydrogels, pastes, ointments, creams, plasters, drenches,osmotic delivery devices, suppositories, enemas, injectables, implants,sprays, or aerosols. The compositions may be formulated according toconventional pharmaceutical practice (see, e.g., Remington: The Scienceand Practice of Pharmacy, 22nd edition, 2013, ed. L. V. Allen,Pharmaceutical Press, Philadelphia, and Encyclopedia of PharmaceuticalTechnology, 4^(th) Edition, ed. J. Swarbrick, 2013, CRC Press, NewYork).

Each compound may be formulated in a variety of ways that are known inthe art. For example, a compound of the invention and a biologicallyactive agent as defined herein may be formulated together or separately.Desirably, a compound of the invention and a biologically active agentare formulated together for their simultaneous or near simultaneousadministration. In another embodiment, two or more biologically activeagents may be formulated together with a compound of the invention, orseparately. Other examples include, but are not limited to, two or morecompounds of the invention formulated together, wherein the compoundsare formulated together with or without one or more biologically activeagents.

The individually or separately formulated agents can be packagedtogether as a kit. Non-limiting examples include but are not limited tokits that contain, e.g., two pills, a pill and a powder, a suppositoryand a liquid in a vial, two topical creams, etc. The kit can includeoptional components that aid in the administration of the unit dose topatients, such as vials for reconstituting powder forms, syringes forinjection, customized IV delivery systems, inhalers, etc. Additionally,the unit dose kit can contain instructions for preparation andadministration of the compositions.

The kit may be manufactured as a single use unit dose for one patient,multiple uses for a particular patient (at a constant dose or in whichthe individual compounds may vary in potency as therapy progresses); orthe kit may contain multiple doses suitable for administration tomultiple patients (“bulk packaging”). The kit components may beassembled in cartons, blister packs, bottles, tubes, and the like.

Controlled Release Formulations

Each compound of the invention, alone or in combination with one or moreof the biologically active agents as described herein, can be formulatedfor controlled release (e.g., sustained or measured) administration, asdescribed in U.S. Patent Application Publication Nos. 2003/0152637 and2005/0025765, each incorporated herein by reference. For example, acompound of the invention, alone or in combination with one or more ofthe biologically active agents as described herein, can be incorporatedinto a capsule or tablet that is administered to the patient.

Any pharmaceutically acceptable vehicle or formulation suitable forlocal application and/or injection into a site to be treated (e.g., apainful surgical incision, wound, or joint), that is able to provide asustained release of compound of the invention, alone or in combinationwith one or more of the biologically active agents as described herein,may be employed to provide for prolonged elimination or alleviation ofinflammation, as needed. Controlled release formulations known in theart include specially coated pellets, polymer formulations or matricesfor surgical insertion or as sustained release microparticles, e.g.,microspheres or microcapsules, for implantation, insertion, infusion orinjection, wherein the slow release of the active medicament is broughtabout through sustained or controlled diffusion out of the matrix and/orselective breakdown of the coating of the preparation or selectivebreakdown of a polymer matrix. Other formulations or vehicles forcontrolled, sustained or immediate delivery of an agent to a preferredlocalized site in a patient include, e.g., suspensions, emulsions, gels,liposomes and any other suitable art known delivery vehicle orformulation acceptable for subcutaneous or intramuscular administration.

A wide variety of biocompatible materials may be utilized as acontrolled release carrier to provide the controlled release of acompound of the invention, alone or in combination with one or morebiologically active agents, as described herein. Any pharmaceuticallyacceptable biocompatible polymer known to those skilled in the art maybe utilized. It is preferred that the biocompatible controlled releasematerial degrade in vivo within about one year, preferably within about3 months, more preferably within about two months. More preferably, thecontrolled release material will degrade significantly within one tothree months, with at least 50% of the material degrading into non-toxicresidues, which are removed by the body, and 100% of the compound of theinvention being released within a time period within about two weeks,preferably within about 2 days to about 7 days. A degradable controlledrelease material should preferably degrade by hydrolysis, either bysurface erosion or bulk erosion, so that release is not only sustainedbut also provides desirable release rates. However, the pharmacokineticrelease profile of these formulations may be first order, zero order,bi- or multi-phasic, to provide the desired reversible localanti-nociceptive effect over the desired time period.

Suitable biocompatible polymers can be utilized as the controlledrelease material. The polymeric material may comprise biocompatible,biodegradable polymers, and, in certain preferred embodiments, ispreferably a copolymer of lactic and glycolic acid. Preferred controlledrelease materials which are useful in the formulations of the inventioninclude the polyanhydrides, polyesters, co-polymers of lactic acid andglycolic acid (preferably wherein the weight ratio of lactic acid toglycolic acid is no more than 4:1 i.e., 80% or less lactic acid to 20%or more glycolic acid by weight) and polyorthoesters containing acatalyst or degradation enhancing compound, for example, containing atleast 1% by weight anhydride catalyst such as maleic anhydride. Examplesof polyesters include polylactic acid, polyglycolic acid and polylacticacid-polyglycolic acid copolymers. Other useful polymers include proteinpolymers such as collagen, gelatin, fibrin and fibrinogen andpolysaccharides such as hyaluronic acid.

The polymeric material may be prepared by any method known to thoseskilled in the art. For example, where the polymeric material iscomprised of a copolymer of lactic and glycolic acid, this copolymer maybe prepared by the procedure set forth in U.S. Pat. No. 4,293,539,incorporated herein by reference. Alternatively, copolymers of lacticand glycolic acid may be prepared by any other procedure known to thoseskilled in the art. Other useful polymers include polylactides,polyglycolides, polyanhydrides, polyorthoesters, polycaprolactones,polyphosphazenes, polyphosphoesters, polysaccharides, proteinaceouspolymers, soluble derivatives of polysaccharides, soluble derivatives ofproteinaceous polymers, polypeptides, polyesters, and polyorthoesters ormixtures or blends of any of these.

Pharmaceutically acceptable polyanhydrides which are useful in thepresent invention have a water-labile anhydride linkage. The rate ofdrug release can be controlled by the particular polyanhydride polymerutilized and its molecular weight. The polysaccharides may bepoly-1,4-glucans, e.g., starch glycogen, amylose, amylopectin, andmixtures thereof. The biodegradable hydrophilic or hydrophobic polymermay be a water-soluble derivative of a poly-1,4-glucan, includinghydrolyzed amylopectin, derivatives of hydrolyzed amylopectin such ashydroxyethyl starch (HES), hydroxyethyl amylose, dialdehyde starch, andthe like. The polyanhydride polymer may be branched or linear.

Examples of polymers which are useful in the present invention include(in addition to homopolymers and copolymers of poly(lactic acid) and/orpoly(glycolic acid)) poly[bis(p-carboxyphenoxy) propane anhydride](PCPP), poly[bis(p-carboxy)methane anhydride] (PCPM), polyanhydrides ofoligomerized unsaturated aliphatic acids, polyanhydride polymersprepared from amino acids which are modified to include an additionalcarboxylic acid, aromatic polyanhydride compositions, and co-polymers ofpolyanhydrides with other substances, such as fatty acid terminatedpolyanhydrides, e.g., polyanhydrides polymerized from monomers of dimersand/or trimers of unsaturated fatty acids or unsaturated aliphaticacids. Polyanhydrides may be prepared in accordance with the methods setforth in U.S. Pat. No. 4,757,128, incorporated herein by reference.Polyorthoester polymers may be prepared, e.g., as set forth in U.S. Pat.No. 4,070,347, incorporated herein by reference. Polyphosphoesters maybe prepared and used as set forth in U.S. Pat. Nos. 6,008,318,6,153,212, 5,952,451, 6,051,576, 6,103,255, 5,176,907 and 5,194,581,each of which is incorporated herein by reference.

Proteinaceous polymers may also be used. Proteinaceous polymers andtheir soluble derivatives include gelation biodegradable syntheticpolypeptides, elastin, alkylated collagen, alkylated elastin, and thelike. Biodegradable synthetic polypeptides includepoly-(N-hydroxyalkyl)-L-asparagine, poly-(N-hydroxyalkyl)-L-glutamine,copolymers of N-hydroxyalkyl-L-asparagine and N-hydroxyalkyl-L-glutaminewith other amino acids. Suggested amino acids include L-alanine,L-lysine, L-phenylalanine, L-valine, L-tyrosine, and the like.

In additional embodiments, the controlled release material, which ineffect acts as a carrier for a compound of the invention, alone or incombination with one or more biologically active agents as describedherein, can further include a bioadhesive polymer such as pectins(polygalacturonic acid), mucopolysaccharides (hyaluronic acid, mucin) ornon-toxic lectins or the polymer itself may be bioadhesive, e.g.,polyanhydride or polysaccharides such as chitosan.

In embodiments where the biodegradable polymer comprises a gel, one suchuseful polymer is a thermally gelling polymer, e.g., polyethylene oxide,polypropylene oxide (PEO-PPO) block copolymer such as Pluronic™ F127from BASF Wyandotte. In such cases, the local anesthetic formulation maybe injected via syringe as a free-flowing liquid, which gels rapidlyabove 30° C. (e.g., when injected into a patient). The gel system thenreleases a steady dose of a compound of the invention, alone or incombination with one or more biologically active agents as describedherein, at the site of administration.

Dosage Forms for Oral Use

Formulations for oral use include tablets containing the activeingredient(s) in a mixture with non-toxic pharmaceutically acceptableexcipients. These excipients may be, for example, inert diluents orfillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystallinecellulose, starches including potato starch, calcium carbonate, sodiumchloride, lactose, calcium phosphate, calcium sulfate, or sodiumphosphate); granulating and disintegrating agents (e.g., cellulosederivatives including microcrystalline cellulose, starches includingpotato starch, croscarmellose sodium, alginates, or alginic acid);binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid,sodium alginate, gelatin, starch, pregelatinized starch,microcrystalline cellulose, magnesium aluminum silicate,carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethyleneglycol); and lubricating agents, glidants, and antiadhesives (e.g.,magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenatedvegetable oils, or talc). Other pharmaceutically acceptable excipientscan be colorants, flavoring agents, plasticizers, humectants, bufferingagents, taste masking agents (such as hydroxypropyl methylcellulose,hydroxypropyl cellulose), and the like.

One or more compounds of the invention and one or more biologicallyactive agents, as defined herein, may be mixed together in a tablet,capsule, or other vehicle, or may be partitioned. In one example, acompound of the invention is contained on the inside of the tablet, andthe biologically active agent is on the outside of the tablet, such thata substantial portion of the biologically active agent is released priorto the release of the compound of the invention.

Formulations for oral use may also be provided as chewable tablets, oras hard gelatin capsules wherein the active ingredient is mixed with aninert solid diluent (e.g., potato starch, lactose, microcrystallinecellulose, calcium carbonate, calcium phosphate or kaolin), or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example, peanut oil, liquid paraffin, or olive oil.Powders, granulates, and pellets may be prepared using the ingredientsmentioned above under tablets and capsules in a conventional mannerusing, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

Formulations for oral administration to the mouth may also be providedas a mouthwash, an oral spray, oral rinse solution, oral ointment, ororal gel.

Dissolution or diffusion controlled release can be achieved byappropriate coating of a tablet, capsule, pellet, or granulateformulation of compounds, or by incorporating the compound into anappropriate matrix. A controlled release coating may include one or moreof the coating substances mentioned above and/or, e.g., shellac,beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glycerylmonostearate, glyceryl distearate, glycerol palmitostearate,ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetatebutyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone,polyethylene, polymethacrylate, methylmethacrylate,2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol,ethylene glycol methacrylate, and/or polyethylene glycols. In acontrolled release matrix formulation, the matrix material may alsoinclude, e.g., hydrated methylcellulose, carnauba wax and stearylalcohol, carbopol 934, silicone, glyceryl tristearate, methylacrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/orhalogenated fluorocarbon.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally include aqueoussolutions, suitably flavored syrups, aqueous or oil suspensions, andflavored emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil, or peanut oil, as well as elixirs and similarpharmaceutical vehicles.

Generally, when administered to a human, the oral dosage of any of thecompounds of the combination of the invention will depend on the natureof the compound, and can readily be determined by one skilled in theart. Typically, such dosage is normally about 0.001 mg to 2000 mg perday, desirably about 1 mg to 1000 mg per day, and more desirably about 5mg to 500 mg per day. Dosages up to 200 mg per day may be necessary.

Administration of each drug in a combination therapy, as describedherein, can, independently, be one to four times daily for one day toone year, and may even be for the life of the patient. Chronic,long-term administration will be indicated in many cases.

Parenteral Formulations

Formulations suitable for parenteral administration (e.g., byinjection), include aqueous or non-aqueous, isotonic, pyrogen-free,sterile liquids (e.g., solutions, suspensions), in which the compound isdissolved, suspended, or otherwise provided (e.g., in a liposome orother microparticulate). Such liquids may additional contain otherpharmaceutically acceptable ingredients, such as anti-oxidants, buffers,preservatives, stabilizers, bacteriostats, suspending agents, thickeningagents, and solutes which render the formulation isotonic with the blood(or other relevant bodily fluid) of the intended recipient. Examples ofexcipients include, for example, water, alcohols, polyols, glycerol,vegetable oils, and the like. Examples of suitable isotonic carriers foruse in such formulations include Sodium Chloride Injection, Ringer'sSolution, or Lactated Ringer's Injection. Typically, the concentrationof the compound in the liquid is from about 1 ng/ml to about 10 μg/ml,for example from about 10 ng/ml to about 1 g/ml. The formulations may bepresented in unit-dose or multi-dose sealed containers, for example,ampoules and vials, and may be stored in a freeze-dried (lyophilised)condition requiring only the addition of the sterile liquid carrier, forexample water for injections, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules, and tablets.

Topical Formulations

The compositions of the invention, alone or in combination with one ormore of the biologically active agents described herein, can also beadapted for topical use with a topical vehicle containing from between0.0001% and 25% (w/w) or more of active ingredient(s).

In a preferred combination, the active ingredients are preferably eachfrom between 0.0001% to 10% (w/w), more preferably from between 0.0005%to 4% (w/w) active agent. The topical formulation, including but notlimited to a cream, gel, or ointment, can be applied one to four timesdaily, or as needed. Performing the methods described herein, thetopical vehicle containing the composition of the invention, or acombination therapy containing a composition of the invention ispreferably applied to the site of inflammation on the patient. Forexample, a cream may be applied to the hands of a patient suffering fromarthritic fingers.

The compositions can be formulated using any dermatologically acceptablecarrier. Exemplary carriers include a solid carrier, such as alumina,clay, microcrystalline cellulose, silica, or talc; and/or a liquidcarrier, such as an alcohol, a glycol, or a water-alcohol/glycol blend.The therapeutic agents may also be administered in liposomalformulations that allow therapeutic agents to enter the skin. Suchliposomal formulations are described in U.S. Pat. Nos. 5,169,637;5,000,958; 5,049,388; 4,975,282; 5,194,266; 5,023,087; 5,688,525;5,874,104; 5,409,704; 5,552,155; 5,356,633; 5,032,582; 4,994,213;8,822,537, and PCT Publication No. WO 96/40061. Examples of otherappropriate vehicles are described in U.S. Pat. Nos. 4,877,805,8,822,537, and EP Publication No. 0586106A1. Suitable vehicles of theinvention may also include mineral oil, petrolatum, polydecene, stearicacid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, orvegetable oil.

The composition can further include a skin penetrating enhancer, such asthose described in “Percutaneous Penetration enhancers”, (eds. Smith E Wand Maibach H I. CRC Press 1995). Exemplary skin penetrating enhancersinclude alkyl (N,N-disubstituted amino alkanoate) esters, such asdodecyl 2-(N,N dimethylamino) propionate (DDAIP), which is described inpatents U.S. Pat. Nos. 6,083,996 and 6,118,020, which are bothincorporated herein by reference; a water-dispersible acid polymer, suchas a polyacrylic acid polymer, a carbomer (e.g., Carbopol™ or Carbopol940P™, available from B. F. Goodrich Company (Akron, Ohio)), copolymersof polyacrylic acid (e.g., Pemulen™ from B. F. Goodrich Company orPolycarbophil™ from A. H. Robbins, Richmond, Va.; a polysaccharide gum,such as agar gum, alginate, carrageenan gum, ghatti gum, karaya gum,kadaya gum, rhamsan gum, xanthan gum, and galactomannan gum (e.g., guargum, carob gum, and locust bean gum), as well as other gums known in theart (see for instance, Industrial Gums: Polysaccharides & TheirDerivatives, Whistler R. L., BeMiller J. N. (eds.), 3rd Ed. AcademicPress (1992) and Davidson, R. L., Handbook of Water-Soluble Gums &Resins, McGraw-Hill, Inc., N.Y. (1980)); or combinations thereof.

Other suitable polymeric skin penetrating enhancers are cellulosederivatives, such as ethyl cellulose, methyl cellulose, hydroxypropylcellulose. Additionally, known transdermal penetrating enhancers canalso be added, if desired. Illustrative are dimethyl sulfoxide (DMSO)and dimethyl acetamide (DMA), 2-pyrrolidone, N,N-diethyl-m-toluamide(DEET), 1-dodecylazacycloheptane-2-one (AZONE™, a registered trademarkof Nelson Research), N,N-dimethylformamide, N-methyl-2-pyrrolidone,calcium thioglycolate and other enhancers such as dioxolanes, cyclicketones, and their derivatives and so on.

Also illustrative are a group of biodegradable absorption enhancerswhich are alkyl N,N-2-(disubstituted amino) alkanoates as described inU.S. Pat. Nos. 4,980,378 and 5,082,866, which are both incorporatedherein by reference, including: tetradecyl (N,N-dimethylamino) acetate,dodecyl (N,N-dimethylamino) acetate, decyl (N,N-dimethylamino) acetate,octyl (N,N-dimethylamino) acetate, and dodecyl (N,N-diethylamino)acetate.

Particularly preferred skin penetrating enhancers include isopropylmyristate; isopropyl palmitate; dimethyl sulfoxide; decyl methylsulfoxide; dimethylalanine amide of a medium chain fatty acid; dodecyl2-(N,N-dimethylamino) propionate or salts thereof, such as its organic(e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acidaddition salts) and inorganic salts (e.g., acetic, benzoic, salicylic,glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic,methanesulfonic, cyclohexanesulfamic, picric, and lactic acid additionsalts), as described in U.S. Pat. No. 6,118,020; and alkyl2-(N,N-disubstituted amino)-alkanoates, as described in U.S. Pat. Nos.4,980,378 and 5,082,866.

The skin penetrating enhancer in this composition by weight would be inthe range of 0.5% to 10% (w/w). The most preferred range would bebetween 1.0% and 5% (w/w). In another embodiment, the skin penetratingenhancer comprises between 0.5%-1%, 1%-2%, 2%-3%, 3%-4%, or 4%-5%, (w/w)of the composition.

The compositions can be provided in any useful form. For example, thecompositions of the invention may be formulated as solutions, emulsions(including microemulsions), suspensions, creams, ointments, foams,lotions, gels, powders, or other typical solid, semi-solid, or liquidcompositions (e.g., topical sprays) used for application to the skin orother tissues where the compositions may be used. Such compositions maycontain other ingredients typically used in such products, such ascolorants, fragrances, thickeners (e.g., xanthan gum, a fatty acid, afatty acid salt or ester, a fatty alcohol, a modified cellulose, amodified mineral material, KRISGEL100™, or a synthetic polymer),antimicrobials, solvents, surfactants, detergents, gelling agents,antioxidants, fillers, dyestuffs, viscosity-controlling agents,preservatives, humectants, emollients (e.g., natural or synthetic oils,hydrocarbon oils, waxes, or silicones), hydration agents, chelatingagents, demulcents, solubilizing excipients, adjuvants, dispersants,skin penetrating enhancers, plasticizing agents, preservatives,stabilizers, demulsifiers, wetting agents, sunscreens, emulsifiers,moisturizers, astringents, deodorants, and optionally includinganesthetics, anti-itch actives, botanical extracts, conditioning agents,darkening or lightening agents, glitter, humectants, mica, minerals,polyphenols, silicones or derivatives thereof, sunblocks, vitamins, andphytomedicinals.

The compositions can also include other like ingredients to provideadditional benefits and improve the feel and/or appearance of thetopical formulation. Specific classes of additives commonly use in theseformulations include: isopropyl myristate, sorbic acid NF powder,polyethylene glycol, phosphatidylcholine (including mixtures ofphosphatidylcholine, such as phospholipon G), KRISGEL100™ distilledwater, sodium hydroxide, decyl methyl sulfoxide (as a skin penetratingenhancer), menthol crystals, lavender oil, butylated hydroxytoluene,ethyl diglycol reagent, and 95% percent (190 proof) ethanol.

Formulations for Ophthalmic Administration

The compounds of the invention can also be formulated with anophthalmically acceptable carrier in sufficient concentration so as todeliver an effective amount of the active compound or compounds to theoptic nerve site of the eye. Preferably, the ophthalmic, therapeuticsolutions contain one or more of the active compounds in a concentrationrange of approximately 0.0001% to approximately 5% (weight by volume)and more preferably approximately 0.0005% to approximately 0.1% (weightby volume).

An ophthalmically acceptable carrier does not cause significantirritation to the eye and does not abrogate the pharmacological activityand properties of the charged sodium channel blockers.

Ophthalmically acceptable carriers are generally sterile, essentiallyfree of foreign particles, and generally have a pH in the range of 5-8.Preferably, the pH is as close to the pH of tear fluid (7.4) aspossible. Ophthalmically acceptable carriers are, for example, sterileisotonic solutions such as isotonic sodium chloride or boric acidsolutions. Such carriers are typically aqueous solutions contain sodiumchloride or boric acid. Also useful are phosphate buffered saline (PBS)solutions.

Various preservatives may be used in the ophthalmic preparation.Preferred preservatives include, but are not limited to, benzalkoniumpotassium, chlorobutanol, thimerosal, phenylmercuric acetate, andphenylmercuric nitrate. Likewise, various preferred vehicles may be usedin such ophthalmic preparation. These vehicles include, but are notlimited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose,poloxamers, carboxymethyl cellulose and hydroxyethyl cellulose.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, etc., mannitol and glycerin, or any other suitableophthalmically acceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude but are not limited to, acetate buffers, citrate buffers,phosphate buffers, and borate buffers. Acids or bases may be used toadjust the pH of these formulations as needed. Ophthalmically acceptableantioxidants can also be include. Antioxidants include but are notlimited to sodium metabisulfite, sodium thiosulfate, acetylcysteine,butylated hydroxyanisole, and butylated hydroxytoluene.

Formulations for Nasal and Inhalation Administration

The pharmaceutical compositions of the invention can be formulated fornasal or intranasal administration. Formulations suitable for nasaladministration, when the carrier is a solid, include a coarse powderhaving a particle size, for example, in the range of approximately 20 to500 microns which is administered by rapid inhalation through the nasalpassage. When the carrier is a liquid, for example, a nasal spray or asnasal drops, one or more of the formulations can be admixed in anaqueous or oily solution and inhaled or sprayed into the nasal passage.

For administration by inhalation, the active ingredient can beconveniently delivered in the form of an aerosol spray presentation frompressurized packs or a nebulizer, with the use of a suitable propellant,e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit can be determined byproviding a valve to deliver a metered amount, Capsules and cartridgesof, for example, gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

Dry powder compositions for topical delivery to the lung by inhalationmay, for example, be presented in capsules and cartridges of, forexample, gelatin or blisters of, for example, laminated aluminum foil,for use in an inhaler or insufflator. Powder blend formulationsgenerally contain a powder mix for inhalation of the compound of theinvention and a suitable powder base (carrier/diluent/excipientsubstance) such as mono-, di or ploy-saccharides (e.g. lactose orstarch). Use of lactose is preferred. In one embodiment, each capsule orcartridge may contain between about 2 ug to about 100 mg of the compoundof formula (I) optionally in combination with another therapeuticallyactive ingredient. In a preferred embodiment, each capsule or cartridgemay contain between about 10 ug to about 50 mg of the compound offormula (I) optionally in combination with another therapeuticallyactive ingredient. In another embodiment, each capsule or cartridge maycontain between about 20 ug to about 10 mg of the compound of formula(I) optionally in combination with another therapeutically activeingredient. Alternatively, the compound of the invention may bedelivered without excipients.

Suitably, the packaging/medicament dispenser is of a type selected fromthe group consisting of a reservoir dry powder inhaler (RDPI), a singleuse inhaler (e.g., capsule or blister inhaler) a multi-dose dry powderinhaler (MDPI), and a metered dose inhaler (MDI).

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer can be formulated to contain an aqueousmedium, ethanol, aqueous ethanol, or a suitable alternative agent fordispersing, solubilizing, or extending release of the activeingredient(s); a propellant as solvent; and/or a surfactant, such assorbitan trioleate, oleic acid, or an oligolactic acid.

Compositions formulated for nasal or inhalation administration mayinclude one or more taste-masking agents such as flavoring agents,sweeteners, and other strategies, such as sucrose, dextrose, andlactose, carboxylic acids, menthol, amino acids or amino acidderivatives such as arginine, lysine, and monosodium glutamate, and/orsynthetic flavor oils and flavoring aromatics and/or natural oils,extracts from plants, leaves, flowers, fruits, etc. and combinationsthereof. These may include cinnamon oils, oil of wintergreen, peppermintoils, clover oil, bay oil, anise oil, eucalyptus, vanilla, citrus oilsuch as lemon oil, orange oil, grape and grapefruit oil, fruit essencesincluding apple, peach, pear, strawberry, raspberry, cherry, plum,pineapple, apricot, etc. Additional sweeteners include sucrose,dextrose, aspartame, acesulfame-K, sucralose and saccharin, organicacids (by non-limiting example citric acid and aspartic acid). Suchflavors may be present at from about 0.05 to about 4 percent by weight,and may be present at lower or higher amounts as a factor of one or moreof potency of the effect on flavor, solubility of the flavorant, effectsof the flavorant on solubility or other physicochemical orpharmacokinetic properties of other formulation components, or otherfactors.

Indications

The compounds, compositions, methods, and kits of the invention can beused to treat pain, cough or itch associated with any of a number ofconditions, including trigeminal trophic syndrome, erythromelalgia, backand neck pain, lower back pain, cancer pain, gynecological and laborpain, abdominal wall pain, chronic abdominal wall pain, fibromyalgia,allergic rhinitis, arthritis, rheumatoid arthritis, osteoarthritis,rheumatological pains, orthopedic pains, acute and post herpeticneuralgia and other neuropathic pains (including peripheral neuropathy),sickle cell crises, muscle pain, vulvodynia, rectal pain, Levator anisyndrome, proctalgia fugax, peri-anal pain, hemorrhoid pain, stomachpain, ulcers, inflammatory bowel disease, irritable bowel disease,irritable bowel syndrome, oral mucositis, esophagitis, interstitialcystitis, urethritis and other urological pains, dental pain, burn pain,headaches, ophthalmic irritation, conjunctivitis (e.g., allergicconjunctivitis), eye redness, dry eye, dry eye syndrome (chronic ocularpain), complex regional pain syndrome, acute postoperative pain,postoperative pain, post-surgical ocular pain, and procedural pain(i.e., pain associated with injections, draining an abscess, surgery,dental procedures, ophthalmic procedures, ophthalmic irritation,conjunctivitis (e.g., allergic conjunctivitis), eye redness, dry eye,arthroscopies and use of other medical instrumentation, cosmeticsurgical procedures, dermatological procedures, setting fractures,biopsies, and the like).

Since a subclass of nociceptors mediate itch sensation, the compounds,compositions, methods, and kits of the invention can also be used totreat itch in patients with conditions like pruritus (including, but notlimited to, brachioradial, chronic idiopathic, genital/anal, notalgiaparesthetica, and scalp), allergic dermatitis, atopic dermatitis,contact dermatitis, poison ivy, infections, parasites, insect bites,pregnancy, metabolic disorders, liver or renal failure, drug reactions,allergic reactions, eczema, hand eczema, genital and anal itch,hemorrhoid itch, and cancer.

Since a subclass of nociceptors can initiate aberrant cough reflexes,the compounds, compositions, methods, and kits of the invention can alsobe used to treat cough in patients with conditions like asthma, COPD,asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis(IPF), idiopathic pulmonary fibrosis, post viral cough, post-infectioncough, chronic idiopathic cough and lung cancer.

The compounds, compositions, methods, and kits of the invention can alsobe used to treat neurogenic inflammation and neurogenic inflammatorydisorders. Inflammation is a complex set of responses to harmful stimulithat results in localized redness, swelling, and pain. Inflammation canbe innate or adaptive, the latter driven by antigens and is mediated byimmune cells (immune-mediated inflammation). Neurogenic inflammationresults from the efferent functions of pain-sensing neurons(nociceptors), wherein neuropeptides and other chemicals that arepro-inflammatory mediators are released from the peripheral terminals ofthe nociceptors when they are activated. This release process ismediated by calcium influx and exocytosis of peptide containingvesicles, and the pro-inflammatory neuropeptides include substance P,neurokinin A and B (collectively known as tachykinins), calcitoningene-related peptide (CGRP), and vasoactive intestinal polypeptide(VIP).

The release of peripheral terminal chemicals stimulate a variety ofinflammatory responses. First, the release of substance P can result inan increase in capillary permeability such that plasma proteins leakfrom the intravascular compartment into the extracellular space (plasmaextravasation), causing edema. This can be detected as a wheal (a firm,elevated swelling of the skin) which is one component of a triad ofinflammatory responses—wheal, red spot, and flare—known as the Lewistriple response. Second, the release of CGRP causes vasodilation,leading to increased blood flow. This can be detected as a flare, whichis another component of the Lewis triple response.

Substance P also has a pro-inflammatory action on immune cells (e.g.macrophages, T-cells, mast cells, and dendritic cells) via theirneurokinin-1 (NK1) receptor. This effect has been documented in allergicrhinitis, gastritis, and colitis, and represents an interface betweenthe neurogenic and immune-mediated components of inflammation. SubstanceP released from one nociceptor may also act on NK1 receptors onneighboring nociceptors to sensitize or activate them, causing a spreadof activation and afferent/efferent function. These efferent functionsof nociceptors can be triggered by: 1) Direct activation of a nociceptorterminal by a peripheral adequate stimulus applied to the terminal (e.g.a pinch); 2) Indirect antidromic activation of a non-stimulatednociceptor terminal by the axon reflex, wherein action potential inputfrom one terminal of a nociceptor, upon reaching a converging axonalbranch point in the periphery, results in an action potential travelingfrom the branch point down to the peripheral terminal of anon-stimulated terminal; and 3) Activation as a result of activity innociceptor central terminals in the CNS traveling to the periphery(e.g., primary afferent depolarization of central terminals produced byGABA can be sufficient to initiate action potentials traveling the“wrong way”).

Genomic analysis of lung resident ILC2 cells has revealed expression ofreceptors for several neuropeptides released by sensory neurons,including SP, CGRP and VIP, providing an opportunity for nociceptors todirectly communicate with these cells. In particular, VIP is found to beexpressed in NaV1.8+ nodose ganglion neurons, including lung afferentsin OVA-exposed mice. Cultured nodose ganglion neurons stimulated withcapsaicin or IL5 also released VIP while BALF from OVA-exposed micecontained elevated VIP compared to vehicle-challenged mice (Talbot etal., Neuron. 2015 Jul. 15; 87(2): 341-354). These data indicate that VIPis released in the inflamed lung and can be blocked by silencing neuronswith charged sodium channel blockers of the present invention. Inaddition, when CD4+ T cells cultured under T_(H)2 skewing conditionswere exposed to recombinant mouse VIP, the transcript levels of IL-13and IL-5 increased, suggesting that VIP contributes to the competence ofT_(H)2 cells to transcribe these type II regulatory cytokines.

Immune mediator release from immune cells can also activate nociceptors.Mast cells are found close to primary nociceptive neurons and contributeto nociceptor sensitization in a number of contexts. Injection of thesecretagogue compound 48/80 promotes degranulation of mast cells in thedura and leads to excitation of meningeal nociceptors. Mast celldegranulation also contributes to the rapid onset of nerve growthfactor-induced thermal hyperalgesia. Macrophages contribute tonociceptor sensitization by releasing several soluble mediators.Expression of the chemokine macrophage inflammatory protein-1α (MIP-1α)and its receptors CCR1 and CCR5 is increased in macrophages and Schwanncells after partial ligation of the sciatic nerve and contributes to thedevelopment of neuropathic pain. Lymphocytes contribute to thesensitization of peripheral nociceptors. T cells infiltrate the sciaticnerve and dorsal root ganglion (DRG) after nerve injury. Hyperalgesiaand allodynia induced by nerve injury are markedly attenuated orabrogated in rodents lacking T cells and the immunosuppressant rapamycinattenuates neuropathic pain in rats, partly owing to an effect on Tcells. Among the subsets of T cells, type 1 and 2 helper T cells (T_(H)1and T_(H)2 cells) have been shown to have different roles in neuropathicpain. T_(H)1 cells facilitate neuropathic pain behavior by releasingproinflammatory cytokines (IL-2 and interferon-γ (IFNγ)), whereas T_(H)2cells inhibit it by releasing anti-inflammatory cytokines (IL-4, IL-10and IL-13). The complement system also has a role in inflammatoryhyperalgesia and neuropathic pain. C5a, an anaphylatoxin, is animportant effector of the complement cascade and upon binding to C5aR1receptors on neutrophils it becomes a potent neutrophil attractant (Ren& Dubner, Nat. Med. 16:1267-1276 (2010)).

Bacterial infections have been shown to directly activate nociceptors,and that the immune response mediated through TLR2, MyD88, T cells, Bcells, and neutrophils and monocytes is not necessary for Staphylococcusaureus-induced pain in mice (Chiu et al., Nature 501:52-57 (2013)).Mechanical and thermal hyperalgesia in mice is correlated with livebacterial load rather than tissue swelling or immune activation.Bacteria induce calcium flux and action potentials in nociceptorneurons, in part via bacterial N-formylated peptides and thepore-forming toxin α-haemolysin, through distinct mechanisms. Specificablation of Nav1.8-lineage neurons, which include nociceptors, abrogatedpain during bacterial infection, but concurrently increased local immuneinfiltration and lymphadenopathy of the draining lymph node. Thus,bacterial pathogens produce pain by directly activating sensory neuronsthat modulate inflammation, an unsuspected role for the nervous systemin host-pathogen interactions. Data from Talbot et al., (Neuron. 2015Jul. 15; 87(2): 341-354) have also suggested that nociceptors areactivated during exposure to allergens in sensitized animals.

In certain disorders, neurogenic inflammation contributes to theperipheral inflammation elicited by tissue injury, autoimmune disease,infection, and exposure to irritants in soft tissue, skin, therespiratory system, joints, the urogenital and GI tract, the liver, andthe brain. Neurogenic inflammatory disorders include, but are notlimited to, allergic inflammation, inflammatory bowel disease,interstitial cystitis, atopic dermatitis, asthma, conjunctivitis,arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis,gastritis, migraine headache, psoriasis, rhinitis, rosacea, sunburn,pancreatitis, chronic cough, chronic rhinosinusistis, traumatic braininjury, polymicrobial sepsis, tendinopathies, chronic urticaria,rheumatic disease, acute lung injury, exposure to irritants, inhalationof irritants, pollutants, or chemical warfare agents, as describedherein.

Assessment of Pain, Cough, Itch, and Neurogenic Inflammation

In order to measure the efficacy of any of the compounds, compositions,methods, and kits of the invention in the treatment of pain associatedwith musculoskeletal, immunoinflammatory and neuropathic disorders, ameasurement index may be used. Indices that are useful include a visualanalog scale (VAS), a Likert scale, categorical pain scales,descriptors, the Lequesne index, the WOMAC index, and the AUSCAN index,each of which is well known in the art. Such indices may be used tomeasure pain, itch, function, stiffness, or other variables.

A visual analog scale (VAS) provides a measure of a one-dimensionalquantity. A VAS generally utilizes a representation of distance, such asa picture of a line with hash marks drawn at regular distance intervals,e.g., ten 1-cm intervals. For example, a patient can be asked to rank asensation of pain or itch by choosing the spot on the line that bestcorresponds to the sensation of pain or itch, where one end of the linecorresponds to “no pain” (score of 0 cm) or “no itch” and the other endof the line corresponds to “unbearable pain” or “unbearable itch” (scoreof 10 cm). This procedure provides a simple and rapid approach toobtaining quantitative information about how the patient is experiencingpain or itch. VAS scales and their use are described, e.g., in U.S. Pat.Nos. 6,709,406 and 6,432,937.

A Likert scale similarly provides a measure of a one-dimensionalquantity. Generally, a Likert scale has discrete integer values rangingfrom a low value (e.g., 0, meaning no pain) to a high value (e.g., 7,meaning extreme pain). A patient experiencing pain is asked to choose anumber between the low value and the high value to represent the degreeof pain experienced. Likert scales and their use are described, e.g., inU.S. Pat. Nos. 6,623,040 and 6,766,319.

The Lequesne index and the Western Ontario and McMaster Universities(WOMAC) osteoarthritis index assess pain, function, and stiffness in theknee and hip of OA patients using self-administered questionnaires. Bothknee and hip are encompassed by the WOMAC, whereas there is one Lequesnequestionnaire for the knee and a separate one for the hip. Thesequestionnaires are useful because they contain more information contentin comparison with VAS or Likert. Both the WOMAC index and the Lequesneindex questionnaires have been extensively validated in OA, including insurgical settings (e.g., knee and hip arthroplasty). Their metriccharacteristics do not differ significantly.

The AUSCAN (Australian-Canadian hand arthritis) index employs a valid,reliable, and responsive patient self-reported questionnaire. In oneinstance, this questionnaire contains 15 questions within threedimensions (Pain, 5 questions; Stiffness, 1 question; and Physicalfunction, 9 questions). An AUSCAN index may utilize, e.g., a Likert or aVAS scale.

Indices that are useful in the methods, compositions, and kits of theinvention for the measurement of pain include the Pain Descriptor Scale(PDS), the Visual Analog Scale (VAS), the Verbal Descriptor Scales(VDS), the Numeric Pain Intensity Scale (NPIS), the Neuropathic PainScale (NPS), the Neuropathic Pain Symptom Inventory (NPSI), the PresentPain Inventory (PPI), the Geriatric Pain Measure (GPM), the McGill PainQuestionnaire (MPQ), mean pain intensity (Descriptor DifferentialScale), numeric pain scale (NPS) global evaluation score (GES) theShort-Form McGill Pain Questionnaire, the Minnesota MultiphasicPersonality Inventory, the Pain Profile and Multidimensional PainInventory, the Child Heath Questionnaire, and the Child AssessmentQuestionnaire.

Itch can be measured by subjective measures (VAS, Lickert, descriptors).Another approach is to measure scratch which is an objective correlateof itch using a vibration transducer or movement-sensitive meters.

Cough can be measured by standard questionnaires like the LeicesterCough Questionnaire as well as validated objective instruments tomeasure cough frequency (e.g. VitaloJAK).

Examples

The following examples are intended to illustrate the invention and arenot intended to limit it.

General Abbreviation Definitions

-   ACN acetonitrile-   AcOH acetic acid-   aq. aqueous-   Bn benzyl-   brine saturated sodium chloride solution in water-   ° C. degrees Celius-   δ chemical shift (ppm)-   d deuterium-   DCM dichloromethane-   DIPEA diisopropylethylamine-   DMAP 4-dimethylaminopyridine-   DMSO dimethyl sulfoxide-   ESI electrospray ionization-   Et₂O diethyl ether-   EtOAc ethyl acetate-   g gram-   h hour-   HATU    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxide-   MeOH methanol-   mHz megahertz-   min minute-   ml milliliter-   mmol millimole-   MS mass spectrometry-   m/z mass to charge ratio-   NMR nuclear magnetic resonance-   Pet ether petroleum ether-   RT room temperature-   TLC thin layer chromatography-   UV ultraviolet light

Synthesis of1-benzyl-1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)azepan-1-iumbromide

Synthesis of intermediate methyl 2-(2-bromoacetamido)-3-methylbenzoate

To a stirred solution of methyl 2-amino-3-methyl benzoate (1 g, 6.05mmol) in water (10 mL) was added 2-bromoacetyl bromide (1.832 g, 9.08mmol) drop wise at 0° C. over 10 min. The resulting reaction mixture wasallowed to stir at room temperature for 2 h as progress of the reactionwas monitored by TLC (70% of Ethyl acetate in pet ether, visualisation:UV). The reaction mixture was quenched with saturated NaHCO₃ solution(10 mL) and the precipitated solid was filtered to afford the crudeproduct which was triturated with n-pentane (10 mL) to afford methyl2-(2-bromoacetamido)-3-methylbenzoate (850 mg) as a white solid. Mass(ESI): m/z 286.09 [M+H]⁺.

Synthesis of intermediate methyl 2-(2-(azepan-1-yl)acetamide)-3-methylbenzoate

To a stirred solution of methyl 2-(2-bromoacetamido)-3-methyl benzoate(1 g, 3.494 mmol) in ACN (25 mL) was added azepane (0.415 g, 4.19 mmol)and K₂CO₃ (0.964 g, 6.98 mmol) and the resulting reaction mixture washeated at 90° C. for 16 h as progress of the reaction was monitored byTLC (50% of ethyl acetate in pet ether, visualisation: UV). The reactionmixture was cooled to room temperature and filtered through a bed ofcelite. The filtrate was diluted with ethyl acetate (100 mL) and thenwashed with water (50 mL), dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to afford methyl 2-(2-(azepan-1-yl)acetamide)-3-methylbenzoate (900 mg) as a yellow liquid. Mass (ESI): m/z305.2 [M+H]⁺. ¹H NMR (400 MHz, (CDCl₃) δ ppm 10.29 (s, 1H), 7.74-7.72(m, 1H), 7.41-7.39 (m, 1H), 7.18 (t, 1H), 3.86 (s, 3H), 3.30 (s, 2H),2.84-2.83 (m, 4H), 2.28 (s, 3H), 1.74-1.65 (m, 9H).

Synthesis of 1-benzyl-1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl) azepan-1-ium bromide

To a stirred solution of methyl 2-(2-(azepan-1-yl)acetamide)-3-methylbenzoate (0.2 g, 0.657 mmol) in ACN (5 mL) was addedbenzyl bromide (0.112 g, 0.657 mmol) and the resulting reaction mixturewas heated at 80° C. for 16 h in sealed tube as progress of the reactionwas monitored by TLC (5% of MeOH/DCM, visualisation: UV). The reactionmixture was cooled to room temperature and concentrated under reducedpressure to afford crude product which was triturated with diethyl ether(10 mL) followed by ethyl acetate (5 mL) to afford1-benzyl-1-(2-((2-(methoxycarbonyl)-6-methylphenyl) amino)-2-oxoethyl)azepan-1-ium bromide (180 mg) as an off white solid. Mass (ESI): m/z395.0 [M]⁺. ¹H NMR (400 MHz, (DMSO-d₆) δ ppm 10.32 (s, 1H), 7.68-7.66(m, 3H), 7.57-7.51 (m, 4H), 7.36 (t, 1H), 4.89 (s, 2H), 4.08 (s, 2H),3.82 (s, 3H), 3.75-3.70 (m, 2H), 3.55-3.50 (m, 2H), 2.31 (s, 3H),1.95-1.94 (m, 4H), 1.66-1.65 (m, 4H).

Synthesis of Compounds 2A-13A: Table A

The following Table A provides additional representative examples of theinvention which were synthesized from 2-bromoacetyl bromide, theappropriate azacycloalkane, benzyl bromide, and the appropriatelysubstituted benzoate ester employing procedures described for compound1A.

TABLE A Com- MS (ESI): pound Structure m/z  2A

409.3 [M]⁺  3A

381.2 [M]⁺  4A

395.2 [M]⁺  5A

367.1 [M]⁺  6A

423.2 [M]⁺  7A

423.2 [M]⁺  8A

395.2 [M]⁺  9A

381.2 [M]⁺ 10A

423.2 [M]⁺ 11A

429.2 [M]⁺ 12A

401.2 [M]⁺ 13A

415.2 [M]⁺

Synthesis of1-benzyl-3-(butoxycarbonyl)-1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl) piperidin-1-ium bromide

Synthesis of intermediate butyl piperidine-3-carboxylate

To a stirred solution of piperidine-3-carboxylic acid (1 g, 7.742 mmol)in n-butanol (10 ml) was added thionyl chloride (5 ml) at 0° C. Theresulting reaction mixture was stirred at 100° C. for 16 h as progressof the reaction was monitored by TLC (Mobile phase: 10% MeOH in DCM,Visualization: UV). The reaction mixture was concentrated under reducedpressure to afford crude residue which was basified with saturated aq.NaHCO₃ (50 ml) at 0° C. and extracted with EtOAc (2×100 ml). Thecombined organic extracts were dried over sodium sulphate andconcentrated under reduced pressure to afford butylpiperidine-3-carboxylate (1.32 g) as a pale yellow oil. MS (ESI): 186.36m/z, [M+H]⁺.

Synthesis of intermediate butyl1-(2-((2-(methoxycarbonyl)-6-methylphenyl) amino)-2-oxoethyl)piperidine-3-carboxylate

To a solution of methyl 2-(2-bromoacetamido)-3-methylbenzoate (0.4 g,1.397 mmol) in ACN (20 ml) was added DIPEA (0.723 g, 5.588 mmol) andbutyl piperidine-3-carboxylate (0.388 g, 2.096 mmol) and the resultingreaction mixture was stirred at to 90° C. for 16 h as progress of thereaction was monitored by TLC (Mobile phase: 10% MeOH in DCM,Visualization: UV). The reaction was concentrated under reduced pressureto afford crude residue which was diluted with water (25 ml) andextracted with EtOAc (2×25 ml). The combined organic extracts werewashed with saturated aq. brine (20 ml), dried over sodium sulphate andconcentrated under reduced pressure to afford crude product which waspurified by normal phase flash chromatography (eluted with 2-3% MeOH inDCM) to afford butyl 1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylate (0.32 g, 73%) as light yellowsemi solid. MS (ESI): 391.31 m/z, [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm10.04 (s, 1H), 7.74-7.72 (m, 1H), 7.41-7.40 (m, 1H), 7.20-7.16 (m, 1H),4.10-4.03 (m, 2H), 3.85 (s, 3H), 3.15 (s, 2H), 3.06-3.03 (m, 1H),2.83-2.77 (m, 2H), 2.60-2.50 (m, 1H), 2.50-2.40 (m, 1H), 2.35 (s, 3H),2.1-1.91 (m, 1H), 1.75-1.61 (m, 2H), 1.61-1.54 (m, 3H), 1.38-1.25 (m,3H), 0.90 (t, 3H).

Synthesis of1-benzyl-3-(butoxycarbonyl)-1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)piperidin-1-ium bromide

To a stirred solution of butyl1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylate(0.3 g, 0.768 mmol) in ACN (10 ml) was added benzyl bromide (0.394 g,2.304 mmol) and the resulting reaction mixture was stirred at 90° C. for16 h as progress of the reaction was monitored by TLC (Mobile phase: 10%Methanol in DCM, Visualization: UV). The reaction mixture wasconcentrated under reduced pressure to afford crude product which wastriturated with EtOAc (40 ml) to afford1-benzyl-3-(butoxycarbonyl)-1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl) piperidin-1-ium bromide (85 mg) as an off white solid(mixture of isomers). MS (ESI): m/z 481.3 [M]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.4-10.2 (m, 1H), 7.68-7.52 (m, 6H), 7.38-7.33 (t, 1H),5.00-4.97 (m, 2H), 4.30-4.06 (m, 4H), 3.90-3.78 (m, 4H), 3.70-3.40 (m,3H), 3.32-3.23 (m, 1H), 2.35-2.2 (m, 3H), 2.10-1.90 (m, 3H), 1.65-1.54(m, 3H), 1.36-1.30 (m, 2H), 0.92-0.87 (m, 3H).

Synthesis of3-(butoxycarbonyl)-1-ethyl-1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)piperidin-1-iumiodide

To a stirred solution of butyl1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylate (0.35 g, 0.896 mmol) in ACN (5 ml) was addedethyl iodide (0.838 g, 5.377 mmol) and the resulting reaction mixturewas stirred at 90° C. for 52 h as progress of the reaction was monitoredby TLC (Mobile phase: 10% MeOH in DCM Visualization: UV). The reactionwas concentrated under reduced pressure to afford crude product whichwas triturated with ethyl acetate (30 ml) to afford of3-(butoxycarbonyl)-1-ethyl-1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)piperidin-1-iumiodide (82 mg) as pale brown sticky solid. MS (ESI): m/z 419.2 [M]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.21 (s, 1H), 7.64-7.62 (m, 1H), 7.54-7.53(m, 1H), 7.36-7.32 (m, 1H), 4.39-4.31 (m, 2H), 4.11-4.07 (m, 3H),3.79-3.35 (m, 7H), 3.30-3.2 (m, 2H), 2.25 (s, 3H), 2.2-1.70 (m, 3H),1.59-1.55 (m, 3H), 1.39-1.23 (m, 5H), 0.9-0.87 (m, 3H).

Synthesis of Compounds 16A-27A: Table B.

The following Table B provides additional representative examples of theinvention which were synthesized from the appropriatepiperidine-3-carboxyl carboxylate, methyl or ethyl2-(2-bromoacetamido)-3-methylbenzoate and benzyl bromide or ethyliodide. Compounds were purified by trituration or reverse phase prepHPLC.

TABLE B Compound Structure MS (ESI): m/z 16A

453.2 [M]⁺ 17A

507.2 [M]⁺ 18A

467.23 [M]⁺ 19A

467.2 [M]⁺ 20A

481.3 [M]⁺ 21A

493.2 [M]⁺ 22A

431.2 [M]⁺ 23A

419.2 [M]⁺ 24A

391.2 [M]⁺ 26A

405.2 [M]⁺ 27A

445.2 [M]⁺

Synthesis of1-benzyl-1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)-3-(propylcarbamoyl)piperidin-1-iumbromide

Synthesis of intermediate tert-butyl 3-(propylcarbamoyl)piperidine-1-carboxylate

To a stirred solution N-(tert-butoxycarbonyl)piperidine-3-carboxylicacid (1 g, 4.361 mmol), triethyl amine (1.3239 g, 13.083 mmol) and HATU(1.9899 g, 5.233 mmol) in THE (25 mL) was added propyl amine (0.5156 g,8.722 mmol) at 0° C. and the resulting reaction mixture was stirred for16 hours at RT as progress of the reaction was monitored by TLC, (Mobilephase: 50% ethyl acetate in pet ether, visualisation: ninhydrin active).The reaction was diluted with ethyl acetate (50 mL) and washed twicewith water (20 mL). The organic layer was dried over anhydrous sodiumsulphate and concentrated under reduced pressure to afford crude whichwas purified by normal phase flash column chromatography (eluted with10%-15% of ethyl acetate in pet. ether) to afford tert-butyl3-(propylcarbamoyl) piperidine-1-carboxylate (1.01 g) as a light-yellowoil. Mass (ESI): m/z 271.45 [M+H]⁺.

Synthesis of intermediate n-propylpiperidine-3-carboxamide

To a stirred solution of tert-butyl 3-(isobutylcarbamoyl)piperidine-1-carboxylate (500 mg, 1.849 mmol) in DCM (10 mL) was addedtrifluoroaceticacid (3 mL) and the resulting reaction mixture wasstirred for 16 hours at room temperature as progress of the reaction wasmonitored by TLC, (Mobile phase: 50% ethyl acetate in pet ether,visualization, ninhydrin active). The reaction was concentrated underreduced pressure to afford N-propylpiperidine-3-carboxamide (520 mg) asa TFA salt which was used without further purification. Mass (ESI): m/z171.2 [M]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.36-3.11 (m, 5H), 2.05-2.98(m, 1H), 8.86 (d, 1H), 2.00-1.86 (m, 4H), 1.82-1.74 (m, 1H), 0.90 (d,6H).

Synthesis of intermediate methyl3-methyl-2-(2-(3-(propylcarbamoyl)piperidin-1-yl) acetamido)benzoate

To a stirred solution of methyl 2-(2-bromoacetamido)-3-methylbenzoate(0.4 g, 1.397 mmol) and DIPEA (0.973 mL, 5.588 mmol) in acetonitrile (20mL) was added N-propylpiperidine-3-carboxamide TFA salt (0.4374 g,1.5377 mmol) and the resulting reaction mixture was heated to 90° C. for16 hours in a sealed tube as progress of the reaction was monitored byTLC, (Mobile phase: 10% MeOH in DCM, visualization: UV). The reactionwas cooled to room temperature and concentrated under reduced pressureto afford crude residue. The crude residue was diluted with DCM (80 mL),washed with water (2×15 mL) and brine solution (20 mL), dried overanhydrous sodium sulphate and concentrated under reduced pressure. Thecrude product was purified by normal phase flash chromatography (elutedwith 2%-3% MeOH in DCM) to afford methyl3-methyl-2-(2-(3-(propylcarbamoyl) piperidin-1-yl) acetamido) benzoate(350 mg), as an off pale-yellow oil. Mass (ESI): m/z 376.2 [M]⁺. ¹H NMR(400 MHz, CDCl₃) δ ppm 9.91 (s, 1H), 7.80-7.77 (m, 1H), 7.43 (d, 1H),7.20 (t, 1H), 6.53 (s, 1H), 3.86 (s, 3H), 3.25-3.13 (m, 2H), 2.97 (S,1H), 2.61-2.52 (m, 4H), 2.37 (s, 3H), 1.82-1.72 (m, 4H), 1.59-1.49 (m,3H), 1.46-1.41 (d, 1H), 1.42 (t, 3H).

Synthesis of1-benzyl-1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)-3-(propylcarbamoyl)piperidin-1-iumbromide

To a stirred solution of methyl3-methyl-2-(2-(3-(propylcarbamoyl)piperidin-1-yl)acetamido)benzoate (300mg, 0.7989 mmol) in acetonitrile (10 mL) was added benzyl bromide (410mg, 2.397 mmol) and the resulting reaction mixture was heated to 90° C.for 16 h in a sealed tube as progress of the reaction was monitored byTLC (Mobile phase: 50% ethyl acetate in pet ether, visualization: UV).The reaction mixture was cooled to room temperature and concentratedunder reduced pressure. The resulting crude product was purified bytrituration with ethyl acetate (20 ml) to afford1-benzyl-1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)-3-(propylcarbamoyl) piperidin-1-ium bromide (170 mg)as an off white solid. (mixture of isomers) Mass (ESI): m/z 466.2 [M]⁺.¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.39 (s, 1H), 7.94 (s, 1H), 7.69-7.63(m, 1H), 7.60-7.54 (m, 6H), 7.39-7.32 (m, 1H), 5.07 (d, 1H), 5.02 (d,1H), 4.93-4.90 (m, 2H), 4.18-4.08 (m, 2H), 3.81 (s, 3H), 3.69-3.48 (m,2H), 3.31-3.05 (m, 2H), 3.03-3.00 (m, 3H), 2.29 (s, 3H), 2.03-1.98 (m,2H), 1.44-1.37 (m, 3H), 0.87-0.86 (m, 3H).

Synthesis of1-ethyl-1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)-3-(propylcarbamoyl)piperidin-1-ium

To a stirred solution of methyl 3-methyl-2-(2-(3-(propyl carbonyl)piperidin-1-yl) acetamide) benzoate (0.150 g, 0.399 mmol) inacetonitrile (1.5 ml) was added ethyl iodide (0.124 g, 0.795 mmol) atroom temperature, then the resulting reaction mixture was heated at 90°C. for 16 h in a sealed tube as progress of the reaction was monitoredby TLC (Mobile phase: 10% MeOH in DCM, visualisation: UV). The reactionmixture was concentrated under reduced pressure to afford the crudecompound which was purified by reverse phase Prep. HPLC (Column: XBridge C18 [19*150]5U; Mobile phase (A): 10 mm ammonium bicarbonate;mobile phase (B): ACN; Method: 0/70, 2/70, 8/70, 10/70, 13/100, 20/70,23/70; flow: 18 mL/min; solubility: ACN+MeOH). Pure fractions werecombined and lyophilized to afford(1-ethyl-1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)-3-(propylcarbamoyl) piperidin-1-ium carbonate (13 mg)as a white gum (mixture of isomers). MS (ESI): m/z 404.3 [M]⁺. 1H NMR(400 MHz, DMSO-d₆) δ ppm 8.18-8.08 (m, 1H), 7.62-7.60 (m, 1H), 7.52-7.50(d, 1H), 7.34-7.29 (m, 1H), 6.90 (s, 1H), 4.40-4.37 (d, 2H), 3.82-3.71(m, 7H), 3.68 (s, 1H), 3.32 (s, 1H), 3.11 (m, 2H), 3.05-2.99 (m, 1H),2.26-2.25 (s, 3H), 2.20 (m, 3H), 1.44-1.29 (m, 6H), 0.85-0.81 (m, 3H).

Synthesis of Compounds 30A-56A: Table C.

The following Table C provides additional representative examples of theinvention which were synthesized from the appropriatepiperidine-3-carboxamide, methyl 12-(2-bromoacetamido)-3-methylbenzoateand benzyl bromide or ethyl iodide. Compounds were purified bytrituration, column chromatography or reverse phase prep HPLC.

TABLE C Compound Structure MS (ESI): m/z 30A

424.2 [M]⁺ 31A

438.3 [M]⁺ 32A

466.2 [M]⁺ 33A

452.2 [M]⁺ 34A

506.3 [M]⁺ 35A

408.3 [M]⁺ 36A

480.2 [M]⁺ 37A

492.2 [M]⁺ 38A

480.3 [M]⁺ 39A

508.3 [M]⁺ 40A

452.2 [M]⁺ 41A

492.2 [M]⁺ 42A

506.2 [M]⁺ 43A

478.3 [M]⁺ 44A

390.2 [M]⁺ 45A

430.2 [M]⁺ 46A

376.2 [M]⁺ 47A

446.3 [M]⁺ 48A

418.38 [M]⁺ 49A

390.2 [M]⁺ 50A

404.2 [M]⁺ 51A

444.3 [M]⁺ 52A

430.27 [M]⁺ 53A

418.3 [M]⁺ 54A

416.2 [M]⁺ 55A

362.2 [M]⁺ 56A

444.6 [M]⁺

Synthesis of1-benzyl-1-(1-((2-(methoxycarbonyl)-6-methylphenyl)amino)-1-oxobutan-2-yl)piperidin-1-iumbromide

Synthesis of intermediate 2-bromobutanoyl chloride

To a stirred solution of 2-bromobutanoic acid (7 g, 43.478 mmol) wasadded thionyl chloride (70 ml) drop wise at 0° C. The resulting reactionmixture was stirred at 100° C. for 2 h as progress of the reaction wasmonitored by TLC (70% EtOAc in hexane, Visualization: UV). The reactionmixture was concentrated under reduced pressure to afford crude2-bromobutanoyl chloride (8.5 g) which was carry forwarded to next stepimmediately.

Synthesis of intermediate methyl 2-(2-bromobutanamido)-3-methylbenzoate

To a stirred solution of 2-bromobutanoyl chloride (4.2656 g, 23.001mmol) in dichloromethane (15 ml) was added methyl2-amino-3-methylbenzoate (1 g, 6.053 mmol) and the resulting reactionmixture was stirred at room temperature for 1 hour as progress of thereaction was monitored by TLC (30% EtOAc in hexane, visualization: UV).The reaction mixture was concentrated under reduced pressure to affordcrude product which was diluted with dichloromethane (100 ml) and washedwith aq. Saturated NaHCO₃ solution (50 ml) followed by water (20 ml×3).The organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford methyl2-(2-bromobutanamido)-3-methylbenzoate (1.82 g) as a pale-yellow gummysolid. MS (ESI): m/z 314.18 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.55(s, 1H), 7.82 (d, 1H), 7.44 (d, 1H), 7.24-7.20 (m, 1H), 4.41-4.38 (m,1H), 3.89 (s, 3H), 2.31-2.22 (m, 4H), 2.20-2.10 (m, 1H), 1.10 (t, 3H).

Synthesis of intermediate methyl 3-methyl-2-(2-(piperidin-1-yl)butanamido) benzoate

To a stirred solution of methyl 2-(2-bromobutanamido)-3-methylbenzoate(1.5 g, 4.77 mmol) and DIPEA (1.234 g, 1.66 mL, 9.548 mmol) inacetonitrile (20 ml) was added piperidine (0.447 g, 0.51 ml, 5.251 mmol)and the resulting reaction mixture was stirred at 90° C. for 16 hours ina sealed tube as progress of the reaction was monitored by TLC (40%EtOAc in hexane, Visualization: UV). The reaction mixture wasconcentrated under reduced pressure to afford the crude residue whichwas diluted with EtOAc (100 ml) and washed with water (20 ml×3). Theorganic phase was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to afford methyl 3-methyl-2-(2-(piperidin-1-yl)butanamido) benzoate (1.72 g) as a gummy solid. MS (ESI): m/z 319.02[M+H]⁺.

Synthesis of 1-benzyl-1-(1-((2-(methoxycarbonyl)-6-methylphenyl)amino)-1-oxobutan-2-yl) piperidin-1-ium bromide

To a stirred solution of methyl 3-methyl-2-(2-(piperidin-1-yl)butanamido) benzoate (1.4 g, 4.396 mmol) in acetonitrile (15 ml) wasadded benzyl bromide (3.759 g, 21.983 mmol) and the resulting reactionmixture was stirred at 90° C. for 16 hours in a sealed tube as progressof the reaction was monitored by TLC (80% EtOAc in hexane,Visualization: UV). The reaction mixture was concentrated under reducedpressure to afford the crude product which was triturated with ethylacetate (3×30 ml) to afford1-benzyl-1-(1-((2-(methoxycarbonyl)-6-methylphenyl)amino)-1-oxobutan-2-yl) piperidin-1-ium bromide (93.8 mg) as an offwhite solid. MS (ESI): m/z 409.29 [M]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.53 (s, 1H), 7.58-7.51 (m, 7H), 7.33 (t, 1H), 5.32 (d, 1H), 4.60 (d,1H), 4.38-4.15 (m, 1H), 3.87-3.80 (m, 4H), 3.73-3.68 (m, 1H), 3.21-3.20(m, 2H), 2.39-2.36 (m, 1H), 2.27 (s, 3H), 2.21-1.94 (m, 5H), 1.55-1.53(m, 2H), 1.09-1.06 (m, 3H).

Synthesis of1-(3-ethylbenzyl)-1-(1-((2-(methoxycarbonyl)-6-methylphenyl)amino)-1-oxobutan-2-yl)piperidin-1-ium formate

To a stirred solution of methyl 3-methyl-2-(2-(piperidin-1-yl)butanamido) benzoate (0.08 g, 0.251 mmol) in acetonitrile (2 ml) wasadded 4-ethyl benzyl bromide (0.0601 g, 0.3017 mmol) and the resultingreaction mixture was stirred at 90° C. for 16 h in a sealed tube asprogress of the reaction was monitored by TLC (80% EtOAc in pet ether,visualization: UV). The reaction mixture was cooled to room temperatureand concentrated under reduced pressure to afford crude product whichwas purified by reverse phase Prep HPLC (Column: X-Select CSH C18(150*25) mm, 10u; mobile phase A: 0.1% FA in Water (Aq); mobile phase B:acetonitrile; flow: 19 ml/min; method (T/% of B): 0/20, 2/20, 10/50,12/50, 12.2/98, 16/98, 16.2/20, 19/20; solubility: ACN+Water+THF;temperature: ambient). Pure fractions were lyophilized to afford1-(3-ethylbenzyl)-1-(1-((2-(methoxycarbonyl)-6-methylphenyl)amino)-1-oxobutan-2-yl) piperidin-1-ium formate (36 mg) as an off whitesolid. Mass (ESI): m/z 437.2 [M]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.3(bs, 1H), 8.45 (bs, 1H), 7.55-7.39 (m, 4H), 5.31 (d, 1H), 4.57 (d, 2H),3.80 (s, 5H), 3.39-3.24 (m, 2H), 2.68 (q, 2H), 2.33-2.27 (m, 5H),2.07-1.9 (m, 4H), 1.6-1.4 (m, 2H), 1.35 (t, 3H), 1.05 (t, 3H).

Synthesis of 1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)-1-(2-(methylamino)-2-oxoethyl)-3-phenylpiperidin-1-iumbromide

Synthesis of intermediate methyl 3-methyl-2-(2-(3-phenylpiperidin-1-yl)acetamido) benzoate

To a stirred solution of methyl 2-(2-bromoacetamido)-3-methylbenzoate (1g, 3.494 mmol) in ACN (10 mL) was added potassium carbonate (1.44 g,10.482 mmol) followed by 3-phenylpiperidine (845 mg, 5.242 mmol) and thereaction mixture was stirred at 90° C. for 16 h in a sealed tube asprogress of the reaction was monitored by TLC (50% EtOAc in pet. ether,Visualization: UV). The reaction mixture was diluted with water (150mL), extracted with EtOAc (2×150 mL), and the combined organic extractswere washed with brine (100 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford methyl3-methyl-2-(2-(3-phenylpiperidin-1-yl) acetamido) benzoate (1.2 g).MS(ESI): m/z 367.28 [M+1]⁺.

Synthesis of 1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)-1-(2-(methylamino)-2-oxoethyl)-3-phenylpiperidin-1-iumbromide

To a stirred solution of methyl 3-methyl-2-(2-(3-phenylpiperidin-1-yl)acetamido) benzoate (250 mg, 0.682 mmol) in ACN (3 mL) was added2-bromo-N-methylacetamide (207 mg, 1.364 mmol) and the reaction mixturewas stirred at 90° C. for 48 h in a sealed tube as progress of thereaction was monitored by TLC (10% MeOH in DCM, Visualization: UV). Thereaction mixture was concentrated under reduced pressure to afford crudecompound which was purified by column chromatography (eluted with 5%MeOH in DCM) to afford pure 1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)-1-(2-(methylamino)-2-oxoethyl)-3-phenylpiperidin-1-iumbromide (120 mg) as a pink gum. (mixture isomers), MS (ESI): m/z 438.2[M]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.32-10.40 (m, 1H), 8.7-8.3 (d,1H), 7.63 (d, 1H), 7.52 (t, 1H), 7.42-7.17 (m, 6H), 4.87-4.57 (m, 4H),4.13-4.01 (m, 2H), 3.75-3.71 (m, 4H), 3.62-3.49 (m, 2H), 2.90-2.82 (m,1H), 2.70-2.60 (m, 3H), 2.25-2.00 (m, 6H), 1.97-1.77 (m, 1H).

Synthesis of Compounds 60A-65A: Table D.

The following Table D provides additional representative examples of theinvention which were synthesized from methyl3-methyl-2-(2-(3-phenylpiperidin-1-yl) acetamido) benzoate and theappropriate alkyl bromide. Compounds were purified by trituration,column chromatography or reverse phase prep HPLC.

TABLE D MS Com- (ESI): pound Structure m/z 60A

452.3 [M]⁺ 61A

424.2 [M]⁺ 62A

480.3 [M]⁺ 63A

453.2 [M]⁺ 64A

439.2 [M]⁺ 65A

395.2 [M]⁺

Synthesis of 1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)-3-phenylpyridin-1-ium bromide

To a stirred solution of methyl 2-(2-bromoacetamido)-3-methylbenzoate(0.2 g, 0.699 mmol) in ACN (2 ml) was added 3-phenylpyridine (0.079 g,1.048 mmol) and the resulting reaction mixture was heated at 80° C. for16 h as progress of the reaction was monitored by TLC (10% MeOH in DCM,visualization: UV). The reaction mixture was concentrated under reducedpressure to afford crude product which was triturated with ethyl acetate(20 ml) to afford pure1-(2-((2-(methoxycarbonyl)-6-methylphenyl)amino)-2-oxoethyl)-3-phenylpyridin-1-iumbromide (0.150 g) as an off white solid. MS (ESI): m/z 361.1 [M]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.37 (s, 1H), 9.46 (s, 1H), 9.00 (q, 2H),8.31 (q, 1H), 7.91 (t, 2H), 7.66-7.59 (m, 4H), 7.52 (d, 1H), 7.32 (s,1H), 5.75 (s, 2H), 3.74 (s, 3H), 2.31 (s, 3H).

Synthesis of Compounds 67A-72A: Table E

Table E provides additional representative examples of the inventionwhich were synthesized from the appropriate2-(2-bromoacetamido)-3-methylbenzoate and heterocycle.

TABLE E Compound Structure MS (ESI): m/z 67A

375.1 [M]⁺ 68A

411.1 [M]⁺ 69A

356.2 [M]⁺ 70A

370.2 [M]⁺ 71A

403.2 [M]⁺ 72A

398.2 [M]⁺

Example 2—Inhibition of Nav1.7 Current

Representative compounds of the invention were synthesized according tothe described methods and tested for the ability to inhibitvoltage-gated sodium channels.

Cell CULTURE

NaV1.7 was expressed upon induction with tetracycline. Cells werecultured in DVEM containing 10% dialyzed Fetal Bovine Serum (VWR,Radnor, Pa.), 100Glutamax (VWR, Radnor, Pa.), 1% Penicillin-Streptomycin(VWR, Radnor, Pa.), 100 mg/L Hygromycin (Thermo Fisher Scientific,Waltham, Mass. and 5 mg/L Blasticidin (Alfa Aesar, Haverhill, Mass.).Cells were grown and maintained at 37° C. in a humidified environmentcontaining 10% CO₂ in air. Cells were detached from the culture flaskfor passage and harvested using 0.05% Trypsin-EDTA (Thermo FisherScientific, Waltham, Mass.). To induce NaV1.7, cells were induced withtetracycline (0.1-1 μg/mL, IBI Scientific, Peosta, Iowa) the day beforerecording and plated onto 24-well plates. Cells were washed with DPBS(VWR, Radnor, Pa.), trypsinized and then triturated five times in 10 mLof growth media to break apart cell aggregates. For one 24-well plate, 2mL of cell suspension was mixed with 23 mL of fresh growth media and0.1-1 μg/mL tetracycline added. 1 ml of mixed media with cells was thenadded to each well of a 24-well plate, with a 12 mm coverslip alreadyplaced in the bottom of the well. Cells were then incubated in 37° C.and 10% CO₂ overnight.

Patch Clamp Solutions & Drugs

The intracellular solution contained the following (in mM) CsCl 135,NaCl 10, EGTA 10, HEPES 10, MgCl₂ 2, adjusted to pH 7.2 with CsOH. Theexternal solution was a normal Ringer solution containing (in mM) NaCl155, HEPES 10, glucose 10, KCl 3.5, CaCl₂) 1.5, MgCl₂ 1 adjusted to pH7.4 with NaOH. CsCl is from Alfa Aesar, Haverhill, Mass. All otherchemicals are from Sigma-Aldrich, St. Louis, Mo. In order to test thedegree of internal block by test compounds the compounds were dissolvedin internal solution at the indicated test concentration. In controlexperiments the internal solution did not contain any compound. In orderto test the degree of external block by test compounds the compoundswere dissolved in external solution at the indicated test concentration.

Whole Cell Patch Clamp Protocol

18-24 hours after cells were induced with tetracycline, coverslips wereplaced into a chamber filled with Normal Ringer solution at roomtemperature and the chamber placed on a microscope. Pipettes were pulledfrom borosilicate glass on a P97 puller (Sutter Instrument, Novato,Calif.) and polished with a MF-830 Microforge (Narishige InternationalUSA, Inc, Amityville, N.Y.) to have a resistance of 1.5-2.5 MΩ whenfilled with CsCl internal solution at room temperature. Healthy cells(those that are round and translucent with no visible blemishes) werechosen for seal formation. A seal was formed between the pipette and thecell, and a brief pulse of suction was used to “break in” and establishthe whole-cell configuration. The membrane potential was held at −100 mVbefore the voltage protocol began. Only cells with series resistancebetween 1.5-5 MΩ were retained for analysis. The voltage protocol was asfollows: Cells were held at −100 mV for 12 ms followed by ahyperpolarizing step to −105 mV for 12 ms to monitor the leak. Cellswere then stepped back to −100 mV for 40 ms. Cells were then depolarizedto −20 mV for 10 ms and then returned to −100 mV for 26 ms (The FIGURE).

Internal Block by Test Compounds

Once the recording was started, the voltage protocol was run at 30second intervals for 5 minutes to get a stable baseline. This wasfollowed by four 30-second periods of 5 Hz stimulation of the samevoltage protocol separated by 1 minute of rest which was then followedby 0.33 Hz stimulation after the last train. Currents were recordedusing PatchMaster software with Heka EPC10 (HEKA Electronics, Lambrecht,Germany). Only cells with inward current amplitudes at −20 mV between400 pA and 4 nA were accepted. In addition, cells having leak currentsgreater than 10% of their current amplitudes were discarded.

Data Analysis: Internal Block

The data was plotted using the Patchmaster software (HEKA Electronics,Lambrecht, Germany) and analyzed by plotting the minimum current duringthe voltage step to −20 mV (peak inward current) as a function of time.In order to determine the degree of rundown over the course of anexperiment, the average peak inward current amplitude (2-3 points)before 5 Hz stimulation was designated as the baseline (I_(baseline)).The average peak inward current during the last 2 second of the last 5Hz train was measured (I_(test)). The control fraction current remainingwas calculated by dividing I_(test) by I_(baseline). On each recordingday three cells were tested with control internal solution and theaverage fraction of current remaining calculated (Ctrl fractioncurrent).

To determine the % block produced by test compounds applied internallythe following was done. The average peak inward current amplitude (2-3points) before 5 Hz stimulation was designated as 0% block(I_(0%block)). To correct for the current change under controlconditions, I_(0%block) was multiplied by the average Ctrl fractioncurrent remaining to get the corrected 0% block current. The averagepeak inward current during the last 2 seconds of the last 5 Hz train wasdesignated as the unblocked current (I_(unblocked)). The % block wascalculated using the following equation:(1−I_(unblocked)/(I_(block)*Ctrl fraction current remaining)×100).

Representative examples of the invention were tested for intracellularinhibition of NaV 1.7. Activity Range is 0% inhibition at 1 μM testconcentration: “++++” (>90%), “+++” 90-70%, “++” (70-30%) or “+”(<300%). The results are presented below:

Nav1.7 Intracellular Compound Inhibition 1 ++++ 2 ++++ 3 ++ 4 +++ 5 ++ 6+++ 7 ++++ 9 +++ 10 +++ 14 ++ 15 ++ 16 +++ 23 +++ 24 ++ 26 ++ 27 ++ 28++ 29 ++ 30 ++ 31 ++ 32 ++ 33 ++ 34 ++ 35 ++ 36 ++ 38 ++ 39 + 40 ++ 41 +43 ++ 44 + 45 ++ 46 + 49 + 54 ++ 55 +++ 56 ++ 57 ++ 58 +++ 59 +++ 60 ++61 +++ 62 ++ 63 +++ 64 ++ 65 ++++ 66 +++ 67 +++ 69 ++ 70 ++ 71 ++ 72 ++

External Block by Test Compounds

Once the recording was started, the voltage protocol was run at 30second intervals for 5 minutes to get a stable baseline. This isfollowed by 5 Hz stimulation of the same voltage protocol run until theend of experiment. The test compound is added during the 5 Hzstimulation train making sure to wait until the cell shows stablecurrent rundown rate before addition of the compound. The test compoundis added for 5 minutes before washing out with normal Ringer's solution.Currents were recorded using PatchMaster software with Heka EPC10 (HEKAElectronics, Lambrecht, Germany). Only cells with inward currentamplitudes at −20 mV between 400 pA and 4 nA were accepted. In addition,cells having leak currents greater than 10% of their current amplitudeswere discarded.

Data Analysis: External Block

The data was plotted using the Patchmaster software (HEKA Electronics,Lambrecht, Germany) and analyzed by plotting the minimum current duringthe voltage step to −20 mV (peak inward current) as a function of time.To determine the % block produced by test compounds applied externallythe following was done. After the stable current rundown rate wasestablished during the 5 Hz stimulation train, the Rate_(rundown) wascalculated by dividing the change in peak current amplitude by time. Theaverage peak inward current amplitude (2-3 seconds) before addition ofcompound was used to determine 0% block (I % block). To correct for therundown, I_(0%block) is subtracted by the (Rate_(rundown)*5 min) to getthe corrected 0% block current. The average peak inward current duringthe last 2-3 seconds of the 5 minutes of compound application timebefore washing is the unblocked current (I_(unblocked)). The % block wasthen calculated using the following equation: Fraction currentblock=1−I_(unblocked)/(I_(0%block)−Rate_(rundown)*5 min).

Representative examples of the invention were tested for extracellularinhibition of NaV 1.7. Activity Range is % inhibition: “++++” (>90%),“+++” 90-70%, “++” (70-40%) or “+” (<40%). The results are presentedbelow:

Compound Test Concentration Nav1.7 Extracellular Inhibition  1A  3 μM + 2A  1 μM +  3A 100 μM ++  4A  3 μM +  9A  10 μM + 10A  1 μM ++ 16A  30μM ++ 59A  10 μM + 61A 100 μM ++ 65A  10 μM ++ 66A  30 μM ++ 67A  10 μM+

Automated Patch Clamp: Cell Culture

NaV1.7 was expressed in HEK293 cells upon induction with tetracycline.Cells were cultured in DMEM containing 10% dialyzed Fetal Bovine Serum(VWR, Radnor, Pa.), 1% Glutamax (VWR, Radnor, Pa.), 1%Penicillin-Streptomycin (VWR, Radnor, Pa.), 100 mg/L Hygromycin (ThermoFisher Scientific, Waltham, Mass. and 5 mg/L Blasticidin (Alfa Aesar,Haverhill, Mass.). Cells were grown and maintained at 37° C. in ahumidified environment containing 10% CO₂ in air. Cells were detachedfrom the culture flask for passage and harvested using 0.05%Trypsin-EDTA (Thermo Fisher Scientific, Waltham, Mass.). To induceNaV1.7, cells were induced with tetracycline (0.1-1 μg/mL, IBIScientific, Peosta, Iowa) the day before recording.

Before experiments, cells were washed with DPBS (VWR, Radnor, Pa.),digested with Detachin (VWR Radnor, Pa.) and then triturated 10 times inCHO Serum-Free Media (VWR Radnor, Pa.) to resuspend the cells and tobreak apart cell aggregates. Cells were counted and the finalconcentration was set at 2-5 million cells per mL.

Patch Clamp Solutions & Drugs

The intracellular solution contained the following: 140 mM CsF, 1 mM/5mM EGTA/CsOH, 10 mM HEPES, 10 mM NaCl, adjusted to pH 7.3 with CsOH, andosmolality to 320 with sucrose. The external solution contained thefollowing: 145 mM NaCl, 4 mM KCl, 1 mM MgCl2, 2 mM CaCl₂), 10 mM HEPES,10 mM Glucose, adjusted to pH 7.4 with CsOH and osmolality to 305 withsucrose. All chemicals are from Sigma-Aldrich, St. Louis, Mo. In orderto test the degree of internal block by test compounds, the compoundswere dissolved in internal solution at the indicated test concentration.In control experiments the internal solution did not contain anycompound. In order to test the degree of external block by testcompounds the compounds were dissolved in external solution at theindicated test concentration.

Automated Patch Clamp Assay Protocol

Automated Patch Clamps were performed on Qube 384 (Sophion Bioscience,Woburn Mass.) with multihole Qchips at a temperature setting of 22degrees. The whole cells configuration was formed with default Qube sealand break-in parameter. The membrane potential was held at −100 mVbefore the voltage protocol began. Two voltage protocols were followed.

Step 1: Cells were held at −100 mV with a depolarized pulse to −20 mVfor 10 ms, the interval was set at 5 s. Currents were corrected bydefault leak subtraction from every pulse. The duration was set at 5mins.

Step 2: Cells were held at −100 mV with a depolarized pulse to −20 mVfor 10 ms. The frequency was 5 Hz. Currents were corrected by leaksubtraction calculated before step 2. The duration was set at 4 mins.

Internal Block by Test Compounds

After Step 2, the Qchip was removed from the recording chamber. Theinternal solution was changed with solutions containing test compounds.Qchips were held at −100 mV without pulsing after being replaced in therecording chamber. The total solution switching time was 8 minutes.After the internal solution exchange, Cells were recorded and step 2 forrepeated for 10 minutes.

Data analysis was performed by Sophion Analyzer. Cells were filteredwith minimum 50 MOhm seal resistance and minimum 5 nA starting current.The rundown of the currents was corrected with control cells (Non-Drug).The remaining was calculated by averaging last 3 points in the end ofexperiments. The base line was calculated as the average of last 3points of Step 2. IC₅₀ curves were plotted with DR-plots/Hill function(a dose-response plot with a Hill fit).

Representative examples of the invention were tested for intracellularinhibition of NaV 1.7 in the automated patch clamp assay. Activity Rangeis reported as IC₅₀: “++++” (<1 μM), “+++” (1-3 μM), “++” (3-10 μM) or“+” (10-30 μM).

Nav1.7 Intracellular Compound Inhibition 1 ++++ 2 ++++ 3 +++ 4 ++++ 5+++ 6 +++ 7 ++++ 8 +++ 9 ++++ 14 +++ 15 +++ 16 ++++ 17 ++ 18 +++ 19 ++++20 +++ 21 ++ 22 +++ 23 ++++ 26 +++ 27 +++ 28 ++++ 30 ++++ 31 ++++ 32++++ 33 ++++ 34 +++ 35 +++ 36 +++ 37 +++ 40 ++++ 41 +++ 42 +++ 43 +++ 45++++ 46 ++ 48 +++ 50 +++ 51 +++ 52 +++ 53 +++ 54 +++ 55 ++ 56 +++ 57 +++58 ++ 59 ++++ 60 ++++ 61 ++++ 62 +++ 63 ++++ 64 ++++ 65 ++++ 66 ++++ 67++++ 68 ++ 69 ++++ 71 +++ 72 +++

External Block by Test Compounds

After Step 2, the external solution was changed with solutionscontaining test compounds. Qchips were held at −100 mV without pulsing.The total solution switching time was 8 minutes. After the externalsolution exchange, cells were recorded using the same procedure as step2 for 10 minutes.

Data analysis was performed by Sophion Analyzer. Data were correctedwith control cells (Non-Drug). The IC₅₀ data were plotted withDR-plots/Hill function (a dose-response plot with a Hill fit).

Representative examples of the invention were tested for extracellularinhibition of NaV 1.7 in the automated patch clamp assay. Activity Rangeis reported as IC₅₀: “++++” (<1 μM), “+++” (1-10 μM), “++” (10-30 μM) or“+” (>30 μM).

Nav1.7 Extracellular Compound Inhibition 1 +++ 2 +++ 3 + 4 +++ 5 + 7 +++8 +++ 9 +++ 16 +++ 23 + 28 ++ 30 + 31 + 32 + 36 ++ 45 + 55 + 57 + 63 +++65 ++ 66 ++ 69 + 71 +++ 72 +++

Example 3—Membrane Permeability

The PAMPA assay (pION, Inc., Woburn Mass.) was used to determine theability of compounds of the invention to cross an artificial lipidmembrane by passive diffusion. Test compounds were dissolved in DMSO (10mM) and diluted 200-fold in buffer (pION Inc., pH 7.4) to provide 50 uMstock solutions. Buffer (150 μL) was added to a UV blank plate and stocksolutions (150 μL) were transferred to a UV reference plate. The blankand reference spectrum were read using a spectrophotometer. Stocksolutions (200 μL) were added to the donor plate of the PAMPA sandwichplate and an accept plate painted with GIT lipid (pION Inc, 5 μL) wasplaced on top. Buffer (200 μL) was added to the acceptor plate and thePAMPA sandwich plate was incubated for 4 hours. Aliquots (150 μL) fromthe acceptor plate were added to a UV plate and read as acceptorspectrum. Aliquots (150 μL) of the donor solutions were added to a UVanalysis plate and read as donor spectrum. The permeability coefficientof test compounds was calculated using PAMPA Explorer™ software (version3.5.0.4) based on the AUC of the reference plate, the donor plate, andthe acceptor plate.

The PAMIPA permeability results (10⁻⁶ cm/s) of representative compoundsare reported as “+” (<0.1 10⁻⁶ cm/s), “++” (0.1-2.0 10⁻⁶ cm/s), “+++”(2.0-10.0 10⁻⁶ cm/s) or “++++” (>10.0 10⁻⁶ cm/s).

PAMPA Compound (10⁻⁶ cm/s) 1 + 2 + 3 + 4 + 5 +++ 6 + 7 + 8 + 9 + 10 +14 + 15 + 16 + 17 +++ 18 + 20 + 21 + 22 + 23 + 24 + 26 + 27 + 28 +++ 29++ 30 + 31 + 32 + 33 ++ 34 + 35 ++ 36 +++ 37 + 38 + 39 + 40 + 41 + 42 +43 + 44 + 45 + 46 + 47 + 48 + 49 + 50 + 51 + 52 + 53 + 54 + 55 + 56 +57 + 58 + 59 + 60 + 61 + 62 + 63 +++ 64 + 65 + 66 + 67 +++ 68 +++ 69 ++70 + 71 + 72 +

The patent and scientific literature referred to herein establishes theknowledge that is available to those with skill in the art. All UnitedStates patents and published or unpublished United States patentapplications cited herein are incorporated by reference. All publishedforeign patents and patent applications cited herein are herebyincorporated by reference. All other published references, documents,manuscripts and scientific literature cited herein are herebyincorporated by reference.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims. It will also be understood that noneof the embodiments described herein are mutually exclusive and may becombined in various ways without departing from the scope of theinvention encompassed by the appended claims.

What is claimed is:
 1. A compound represented by Formula (I)

wherein: Y⁻ is a pharmaceutically acceptable anion; R^(A) is CO₂R^(T);R^(T) is substituted or unsubstituted alkyl; R^(B) is H, D, halogen, orsubstituted or unsubstituted alkyl; R^(C) is selected from as H, D,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, OR^(I), CN, NR^(J)R^(K), NR^(L)C(O)R^(M), S(O)R^(N),S(O)₂R^(N), SO₂R^(O)R^(P), SO₂NR^(Q)R^(R), SO₃R^(S), CO₂R^(T);C(O)R^(U), and C(O)NR^(V)R^(W); each of R^(I), R^(J), R^(K), R^(L),R^(M), R^(N), R^(O), R^(P), R^(Q), R^(R), R^(S), R^(U), R^(V), and R^(W)is independently selected from H, D, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl; or R^(J) and R^(K) or R^(V) and R^(W) orR^(Q) and R^(R) can also be taken together with the nitrogen to whichthey are attached to form a substituted or unsubstituted 5, 6, 7, or 8membered ring; X is —NR^(Z)C(O)—; R^(Z) is H, D, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl;each of R^(D) and R^(E) is independently selected from H, D, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheteroalkyl, and substituted or unsubstituted cycloalkyl; or R^(D) andR^(E) together with the carbon to which they are attached form asubstituted or unsubstituted cycloalkyl or a substituted orunsubstituted heterocyclic; or R^(D) and R^(Z) together with the carbonand the —NC(O)— to which they are attached form a substituted orunsubstituted lactam; each of R^(F), R^(G) and R^(H) is independentlyselected from absent, H, D, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted —C₆-C₁₀ aryl, substituted or unsubstituted5- to 10-membered heteroaryl, substituted or unsubstituted —CH₂—C₅-C₁₀aryl, and substituted or unsubstituted —CH₂—C₅-C₁₀ heteroaryl; oralternatively, two or three of R^(F), R^(G) and R^(H) together with theN⁺ to which they are attached form an optionally substitutedheterocyclyl having, zero, one or more heteroatoms in addition to theN⁺; or two or three of R^(D), R^(E), R^(F), R^(G) and R^(H) togetherwith the N⁺ form an optionally substituted heterocyclic ring having,zero, one or more heteroatoms in addition to the N⁺, including but notlimited to, a heteroaryl ring.
 2. The compound of claim 1, wherein R^(T)is methyl or ethyl.
 3. The compound of claim 1, wherein X¹ is —NHC(O)—.4. The compound of claim 1, wherein R^(B) is methyl, and R^(C) isselected from the group consisting of hydrogen, methyl, halogen,nitrile, methoxy, and ethoxy.
 5. The compound of claim 1, wherein R^(B)are methyl and R^(C) is hydrogen.
 6. The compound of claim 1, whereineach of R^(D) and R^(E) is independently selected from hydrogen, D,substituted or unsubstituted alkyl; or R^(D) and R^(E) together form asubstituted or unsubstituted C₃-C₆ cycloalkyl or substituted orunsubstituted heterocyclic.
 7. The compound of claim 6, wherein R^(D)and R^(E) are both hydrogen.
 8. The compound of claim 6, wherein R^(D)is hydrogen and R^(E) is a C₁-C₄alkyl.
 9. The compound of claim 8,wherein R^(D) is hydrogen and R^(E) is methyl, ethyl, n-propyl, orn-butyl.
 10. The compound of claim 6, wherein R^(D) and R^(E) are takentogether with the carbon to which they are attached to form asubstituted or unsubstituted C₃-C₆ cycloalkyl.
 11. The compound of claim1, wherein each of R^(F), R^(G) and R^(H) is the same or different andis selected from a substituted or unsubstituted alkyl, a substituted orunsubstituted aryl, or a substituted or unsubstituted heteroaryl. 12.The compound of claim 11, wherein each of R^(F), R^(G) and R^(H) is thesame.
 13. The compound of claim 1, wherein R^(F) and R^(G) are the sameor different and are each independently a substituted or unsubstitutedalkyl, and R^(H) is a substituted or unsubstituted arylalkyl, or asubstituted or unsubstituted heteroarylalkyl.
 14. The compound of claim1, wherein R^(F) and R^(G) are the same or different and are each asubstituted or unsubstituted alkyl, and R^(H) is:


15. The compound of claim 1, wherein two of R^(F), R^(G) and R^(H)together with the N⁺ to which they are attached form an optionallysubstituted 5- to 10-membered heterocyclic ring having, zero, one, ormore heteroatoms in addition to the N⁺.
 16. The compound of claim 15,wherein R^(F) and R^(G) are taken together with the N⁺ to which they areattached to form a 5-, 6-, or 7-membered heterocyclyl, and R^(H) is anaralkyl or a heteroaralkyl.
 17. The compound of claim 15, wherein R^(F)and R^(G) together with the N⁺ to which they are attached form anoptionally substituted 5- to 10-membered heterocyclic ring having zero,one, or more heteroatoms in addition to the N⁺, and R^(H) is —CH₂—Z;wherein Z is a substituted or unsubstituted aryl or a substituted orunsubstituted heteroaryl.
 18. The compound of claim 17, wherein Z isselected from the group consisting of unsubstituted phenyl, phenylsubstituted by a C₁-C₄ alkyl, halogen, methoxy, ethoxy, and cyano. 19.The compound of claim 15, wherein R^(F) and R^(G) together with the N⁺to which they are attached form a five, six, or seven-memberedammonium-containing heterocyclic ring.
 20. The compound of claim 1,wherein the compound is selected from those in the Table below: Com-pound Structure  1A

 2A

 3A

 4A

 5A

 6A

 7A

 8A

 9A

10A

11A

12A

13A

14A

15A

16A

17A

18A

19A

20A

21A

22A

23A

24A

26A

27A

28A

29A

30A

31A

32A

33A

34A

35A

36A

37A

38A

39A

40A

41A

42A

43A

44A

45A

46A

47A

48A

49A

50A

51A

52A

53A

54A

55A

56A

57A

58A

59A

60A

61A

62A

63A

64A

65A

66A

67A

68A

69A

70A

71A

72A


21. A pharmaceutical composition comprising the compound of claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 22. The composition of claim 21, wherein saidcomposition is formulated for oral, intravenous, intramuscular, rectal,cutaneous, subcutaneous, topical, transdermal, sublingual, nasal,inhalation, vaginal, intrathecal, epidural, or ocular administration.23. A method for treating pain, cough, itch, or a neurogenicinflammatory disorder in a patient, comprising administering to saidpatient an effective amount of a compound of claim
 1. 24. The method ofclaim 23, wherein said pain is selected from the group consisting ofpain due to back and neck pain, lower back pain, cancer pain,gynecological and labor pain, fibromyalgia, arthritis, rheumatoidarthritis, osteoarthritis, rheumatological pains, orthopedic pains,acute and post herpetic neuralgia and other neuropathic pains (includingperipheral neuropathy), sickle cell crises, vulvodynia, peri-anal pain,irritable bowel disease, irritable bowel syndrome, inflammatory boweldisease, oral mucositis, esophagitis, interstitial cystitis, urethritisand other urological pains, dental pain, headaches, trigeminal trophicsyndrome, erythromelalgia, abdominal wall pain, chronic abdominal wallpain, allergic rhinitis, muscle pain, rectal pain, Levator ani syndrome,proctalgia fugax, hemorrhoid pain, stomach pain, skin ulcers, stomachulcers, burn pain, ophthalmic irritation, conjunctivitis (e.g., allergicconjunctivitis), eye redness, dry eye, dry eye syndrome (chronic ocularpain), complex regional pain syndrome, post-surgical ocular pain,postoperative pain, acute postoperative pain, and procedural pain (i.e.,pain associated with injections, draining an abscess, surgery, dentalprocedures, ophthalmic procedures, ophthalmic irritation, conjunctivitis(e.g., allergic conjunctivitis), eye redness, dry eye, arthroscopies anduse of other medical instrumentation, cosmetic surgical procedures,dermatological procedures, setting fractures, biopsies, and the like).25. The method of claim 23, wherein said cough is selected from thegroup consisting of cough in patients with asthma, COPD, asthma-COPDoverlap syndrome (ACOS), interstitial pulmonary fibrosis (IPF),idiopathic pulmonary fibrosis, post viral cough, post-infection cough,chronic idiopathic cough and lung cancer.
 26. The method of claim 23,wherein said itch is selected from the group consisting of itch due topruritus, brachioradial pruritus, chronic idiopathic pruritus,genital/anal pruritus, notalgia paresthetica, scalp pruritus, allergicdermatitis, contact dermatitis, atopic dermatitis, hand eczema, poisonivy, infections, parasites, insect bites, pregnancy, metabolicdisorders, liver or renal failure, drug reactions, allergic reactions,eczema, genital and anal itch, hemorrhoid itch, and cancer.
 27. Themethod of claim 23, wherein said neurogenic inflammatory disorder isselected from the group consisting of allergic inflammation, asthma,chronic cough, conjunctivitis, rhinitis, psoriasis, inflammatory boweldisease, interstitial cystitis, arthritis, colitis, contact dermatitis,diabetes, eczema, cystitis, gastritis, migraine headache, rosacea,sunburn, pancreatitis, chronic rhinosinusistis, traumatic brain injury,polymicrobial sepsis, tendinopathies, chronic urticaria, rheumaticdisease, acute lung injury, exposure to irritants, inhalation ofirritants, pollutants, chemical warfare agents, and atopic dermatitis.28. The method of claim 23, wherein a compound represented by Formula(I) is used in combination with one or more exogenous large porereceptor agonists.